WO1999032103A1 - New use of local anaesthetics against vascular headaches - Google Patents
New use of local anaesthetics against vascular headaches Download PDFInfo
- Publication number
- WO1999032103A1 WO1999032103A1 PCT/SE1998/002299 SE9802299W WO9932103A1 WO 1999032103 A1 WO1999032103 A1 WO 1999032103A1 SE 9802299 W SE9802299 W SE 9802299W WO 9932103 A1 WO9932103 A1 WO 9932103A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- phenoxy
- amine
- propoxy
- isopropyl
- Prior art date
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Definitions
- the present invention is directed to a new use of [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives. More particularly the invention is directed to the use of [(3-alkoxy-phenoxy)- ethylj-dialkylamine derivatives as a medicament for use in the treatment of vascular headaches, and in particular as a medicament for the treatment of migraine.
- Migraine is a disorder that exhibits a spectrum of treatment responses in afflicted individuals. Some sufferers are fortunate and the therapy may be over-the-counter remedies or even non-drug regimens using behavior modification, acupuncture, and hypnosis as instruments of aborting the headache. Bed rest, a darkened room, and the use of cold packs applied to the temporal artery and its branches may modify the attack. Sleep also has a beneficial effect in ending an attack. Most patients, however, will require prescription drugs for relief from the migraine. The symptoms most in need of treatment are the head pain and gastrointestinal symptoms. To a lesser degree, photophobia and the aura warrant treatment; the latter may also be quite disturbing and require treatment although its duration is relatively brief.
- Migraine is also under-treated. Only about 40 percent of females and 30 percent of males utilize prescription drugs (Celentano et al, 1992). However, many of these patients discontinue prescription medication and rely on the over-the-counter remedies.
- the most common drugs which at present are used for the treatment of migraine and other forms of vascular headaches are inter alia triptanes,ergotamine, aspirin, and NSAIDS.
- One major problem with the just mentioned drugs is that they often have an onset time of from 60 minutes and up to 4 hours, which is a disadvantage in therapy of vascular headache conditions such as migraine.
- these drugs are often in forms suitable for oral administration, which often causes problems for the patient since nausea and vomiting is common among patients suffering from migraine, or other forms of vascular headache conditions.
- WO 98/38998 discloses the use of levobupivacaine and ropivacaine in the treatment of migraine. These local anaesthetics are however structurally distinct from the local anaesthetics used in accordance with the present invention.
- the drug used to treat the vascular headache condition should preferably have a fast onset of action, and also as few side effects as possible.
- the problem underlying the present invention is to find a new way of therapy for vascular headache conditions, and in particular migraine.
- a further problem underlying the present invention is to find a new way of therapy providing a fast onset of action, i.e. a fast pain relief as well as relief of other symptoms associated a vascular headache condition, to the patient suffering from the vascular headache condition.
- the present invention is directed to the use of a compound of the formula I
- R represents C 3 -5 alkyl
- R 2 and R 3 independently represent C 1 - 3 alkyl; or a pharmaceutically acceptable salt thereof ;
- a further aspect of the present invention is the use of a compound of the formula I above, for the manufacture of a medicament for use in the treatment of migraine.
- Still a further aspect of the present invention is a method for the treatment of vascular headache conditions, in particular migraine, comprising administering to a subject suffering from said vascular headache condition, an effective amount of a medicament comprising a compound of the formula I as active agent.
- vascular headache is intended to include any kind of vascular headaches, in particular migraine, cluster headache, post-traumatic headache, tension headache, muscular headache and headaches due to vascular diseases.
- migraine should be interpreted according to The International Classsification of Migraine, Headache Classification Committee 1988. However, the specified vascular headache conditions are not to be considered as limiting the invention in any way.
- Cluster headache is most typically defined as the temporal clustering of attacks during periods usually lasting between 2 weeks and 3 months, separated by remissions of at least 14 days, but usually several months - this type of cluster headache is also called “episodic cluster headache”. "Chronic cluster headache” is characterised by absence of remissions of at least 14 days for more than one year (Textbook of pain, p.504, 3 rd edition, 1994).
- Post-traumatic headache is headache caused as a result of some head trauma (Textbook of pain, p.504, 3 rd edition, 1994).
- Treatment headache and “muscular headache” belong to the group of headaches formerly described as “muscle contraction”, “psychogenic”, “stress” or “essential” (Textbook of pain, p. 502, 3rd edition 1994).
- the compounds according to formula I above may also preferably be used for surgery in the nasal area.
- a therapeutic or prophylactic effect shall preferably have been achieved within 15 minutes from the time of administration.
- Patients suffering from vascular headache conditions such as migraine, often get a feeling that an attack of headache is approaching.
- this patient may administer, preferably intranasally, a dosage of a compound of the formula I . Since the active agent of the formula I has a fast onset of action, the attack of approaching headache will be blocked before it has developed into a painful, vascular headache condition.
- the use in accordance with the present invention also encompasses the administration of a compound of the formula I as an acute rescue medicine.
- This means that the use of a compound of the formula I is also effective for therapy of fully developed vascular headache conditions such as migraine.
- the present invention is intended not only to encompass therapeutic treatment of vascular headache conditions, but also prophylactic treatment of vascular headache conditions.
- the medicament comprising a compound of the formula I above as the active agent may be administered in form of a pharmaceutical formulation, further comprising pharmaceutically acceptable carriers, diluents or adjuvants.
- the compound according to formula I above may be administered nasally or intravenously.
- the medicament is administered nasally in form of a spray.
- spray will be appreciated by a person skilled in the art, but includes a solution which is distributed such as to increase the contact area with the nasal mucosa.
- Administration of the medicament in form of drops and powders is a further useful alternative.
- the dose of the active agent of the formula I above will vary depending on the formulation used, as well as on the severity of the vascular headache condition to be treated. A preferred dose is 0.01-200 mg active agent/kg body weight, more preferably 0.1-2 mg active agent/kg body weight. Similar ranges apply if a compound of the formula I is used for prophylactic treatment.
- Preferred compounds for use as active agents in accordance with the present invention are compounds of the formula I selected from anyone of
- pancuronium bromide 0.06 mg/kg pancuronium bromide (Pavulon ).
- the levels of isoflurane, O2, N2O and the end-tidal CO2 (3.5 - 4.5 %) were monitored during the entire experimental period. Core temperature was maintained at 38 ⁇ 0.5 °C with a homeothermic blanket system.
- the animals were prepared to enable electrical stimulations (3 mA, 2ms, 2 Hz for 5 min) of the sciatic nerve of both legs.
- 10 - 20 ⁇ l of isopropyl-methyl-[2-(3-n-propoxy-phenoxy)- ethylj-amine (2 %) in a gel formulation (batch TARO-83-2) or, when needed, the vehicle (batch 106-10-2) were applied on the sciatic nerve distal to the stimulation electrodes 10 min prior to stimulation.
- the nerves were then sectioned proximal to the electrodes, and Evans blue dye (10 mg/ml, kg) was given intravenously 2 min prior to stimulation.
- Assessment of neurogenic inflammation 10 - 20 ⁇ l of isopropyl-methyl-[2-(3-n-propoxy-phenoxy)- ethylj-amine (2 %) in a gel formulation (batch TARO-83-2) or, when needed, the vehicle (batch 106-10-2) were applied on the sciatic nerve distal
- the neurogenic inflammation was assessed 5 min after the end of the stimulation by rating the localized extravasation of Evans Blue in the skin area of the hindpaw innervated by the sciatic nerve, using a 4-point scale as shown in Table 1 below. In a preliminary experiment the inability of the vehicle to block the development of the neurogenic inflammation was checked.
- the gel was prepared by mixing isopropyl-methyl-[2-(3-n-propoxy-phenoxy)-ethyl]-amine and the hydrochloric acid, whereafter a major part of the water was added. The mixture was stirred until all of the isopropyl-methyl-[2-(3-n-propoxy-phenoxy)-ethyI]-amine had dissolved. pH was adjusted to about 4 and the rest of the water was added. The obtained solution was heated to 70 °C, whereafter the hydroxypropylmethylcellulose was added while vigorous stirring. The jelly was finally cooled while stirring, pH was measured and, if necessary, adjusted to 4.0 - 5.5.
- a compound of the formula I above is administered to migraine patients having moderate to severe pain according to the 4 point verbal rating scale (VRS): none, mild, moderate and severe respectively.
- VRS verbal rating scale
- the route of administration is two different types of nasal administration, one anterior application and one dorsonasal application. Each type of administration is having its own placebo control.
- the patient's visual analogue scale (VAS) score is recorded at baseline.
- each patient receives 1 puff in each nostril every 2 minutes for a 10 minute period.
- each patient receives a total of 10 puffs (5 puffs in each nostril) of a compound of the formula I above
- Adverse events are monitored throughout the treatment period as well as at a follow-up visit after administration of the study drug.
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- 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)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0100599A HUP0100599A3 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
KR1020007006721A KR20010024768A (en) | 1997-12-19 | 1998-12-14 | New Use of Local Anaesthetics Against Vascular Headaches |
EEP200000394A EE200000394A (en) | 1997-12-19 | 1998-12-14 | New use of local anesthetics against vascular headaches |
EP98963712A EP1047412A1 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
CA002314452A CA2314452A1 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
AU18981/99A AU1898199A (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
BR9813775-1A BR9813775A (en) | 1997-12-19 | 1998-12-14 | Use of a compound, process for the treatment of a vascular headache condition, and, pharmaceutical composition suitable for use in the treatment of a vascular headache condition. |
IL13651898A IL136518A0 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
SK783-2000A SK7832000A3 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
JP2000525094A JP2001526217A (en) | 1997-12-19 | 1998-12-14 | Novel use of local anesthetics for vascular headache |
PL98341283A PL341283A1 (en) | 1997-12-19 | 1998-12-14 | Novel application domain of locally anaesthetising agents, namely in treating headaches of vascular origin |
IS5534A IS5534A (en) | 1997-12-19 | 2000-06-15 | New use of local anesthetic agents for headache |
NO20003138A NO20003138L (en) | 1997-12-19 | 2000-06-16 | New application of local anesthetics to vascular headaches |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9704770-8 | 1997-12-19 | ||
SE9704770A SE9704770D0 (en) | 1997-12-19 | 1997-12-19 | New use |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999032103A1 true WO1999032103A1 (en) | 1999-07-01 |
Family
ID=20409476
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1998/002299 WO1999032103A1 (en) | 1997-12-19 | 1998-12-14 | New use of local anaesthetics against vascular headaches |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP1047412A1 (en) |
JP (1) | JP2001526217A (en) |
KR (1) | KR20010024768A (en) |
CN (1) | CN1282241A (en) |
AU (1) | AU1898199A (en) |
BR (1) | BR9813775A (en) |
CA (1) | CA2314452A1 (en) |
EE (1) | EE200000394A (en) |
HU (1) | HUP0100599A3 (en) |
ID (1) | ID26703A (en) |
IL (1) | IL136518A0 (en) |
IS (1) | IS5534A (en) |
NO (1) | NO20003138L (en) |
PL (1) | PL341283A1 (en) |
SE (1) | SE9704770D0 (en) |
SK (1) | SK7832000A3 (en) |
TR (1) | TR200001926T2 (en) |
WO (1) | WO1999032103A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001043733A2 (en) * | 1999-12-15 | 2001-06-21 | Levin Bruce H | Compositions, kits, apparatus, and methods for inhibiting cephalic inflammation |
US6432986B2 (en) | 1997-07-21 | 2002-08-13 | Bruce H. Levin | Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches |
US6491940B1 (en) | 1999-01-27 | 2002-12-10 | Bruce H. Levin | Apparatus for administering composition for inhibiting cerebral neurovascular disorders and muscular headaches |
US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
US11028160B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
US11555064B2 (en) | 2014-03-21 | 2023-01-17 | Teva Pharmaceuticals International Gmbh | Treating headache comprising administering an antibody to calcitonin gene-related peptide |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180058777A (en) * | 2015-09-24 | 2018-06-01 | 테바 파마슈티컬스 인터내셔널 게엠베하 | (Persistence) prevention, treatment and reduction of post-traumatic headache |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3105854A (en) * | 1958-11-06 | 1963-10-01 | Ciba Geigy Corp | Meta-substituted phenoxyethylamines |
US3988475A (en) * | 1974-02-05 | 1976-10-26 | Istituto Luso Farmaco D'italia S.R.L. | Phenoxyalkylamines |
WO1997015548A1 (en) * | 1995-10-27 | 1997-05-01 | Astra Aktiebolag | New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics |
-
1997
- 1997-12-19 SE SE9704770A patent/SE9704770D0/en unknown
-
1998
- 1998-12-14 CN CN98812378A patent/CN1282241A/en active Pending
- 1998-12-14 CA CA002314452A patent/CA2314452A1/en not_active Abandoned
- 1998-12-14 HU HU0100599A patent/HUP0100599A3/en unknown
- 1998-12-14 JP JP2000525094A patent/JP2001526217A/en active Pending
- 1998-12-14 IL IL13651898A patent/IL136518A0/en unknown
- 1998-12-14 PL PL98341283A patent/PL341283A1/en unknown
- 1998-12-14 EP EP98963712A patent/EP1047412A1/en not_active Ceased
- 1998-12-14 KR KR1020007006721A patent/KR20010024768A/en not_active Application Discontinuation
- 1998-12-14 BR BR9813775-1A patent/BR9813775A/en not_active IP Right Cessation
- 1998-12-14 ID IDW20001176A patent/ID26703A/en unknown
- 1998-12-14 SK SK783-2000A patent/SK7832000A3/en unknown
- 1998-12-14 WO PCT/SE1998/002299 patent/WO1999032103A1/en not_active Application Discontinuation
- 1998-12-14 EE EEP200000394A patent/EE200000394A/en unknown
- 1998-12-14 AU AU18981/99A patent/AU1898199A/en not_active Abandoned
- 1998-12-14 TR TR2000/01926T patent/TR200001926T2/en unknown
-
2000
- 2000-06-15 IS IS5534A patent/IS5534A/en unknown
- 2000-06-16 NO NO20003138A patent/NO20003138L/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3105854A (en) * | 1958-11-06 | 1963-10-01 | Ciba Geigy Corp | Meta-substituted phenoxyethylamines |
US3988475A (en) * | 1974-02-05 | 1976-10-26 | Istituto Luso Farmaco D'italia S.R.L. | Phenoxyalkylamines |
WO1997015548A1 (en) * | 1995-10-27 | 1997-05-01 | Astra Aktiebolag | New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6432986B2 (en) | 1997-07-21 | 2002-08-13 | Bruce H. Levin | Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches |
US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
US6491940B1 (en) | 1999-01-27 | 2002-12-10 | Bruce H. Levin | Apparatus for administering composition for inhibiting cerebral neurovascular disorders and muscular headaches |
WO2001043733A2 (en) * | 1999-12-15 | 2001-06-21 | Levin Bruce H | Compositions, kits, apparatus, and methods for inhibiting cephalic inflammation |
WO2001043733A3 (en) * | 1999-12-15 | 2002-05-10 | Bruce H Levin | Compositions, kits, apparatus, and methods for inhibiting cephalic inflammation |
US11555064B2 (en) | 2014-03-21 | 2023-01-17 | Teva Pharmaceuticals International Gmbh | Treating headache comprising administering an antibody to calcitonin gene-related peptide |
US11028160B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
US11028161B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
Also Published As
Publication number | Publication date |
---|---|
EP1047412A1 (en) | 2000-11-02 |
NO20003138D0 (en) | 2000-06-16 |
ID26703A (en) | 2001-02-01 |
TR200001926T2 (en) | 2000-11-21 |
KR20010024768A (en) | 2001-03-26 |
IS5534A (en) | 2000-06-15 |
PL341283A1 (en) | 2001-04-09 |
CN1282241A (en) | 2001-01-31 |
AU1898199A (en) | 1999-07-12 |
NO20003138L (en) | 2000-08-18 |
CA2314452A1 (en) | 1999-07-01 |
HUP0100599A3 (en) | 2002-04-29 |
SK7832000A3 (en) | 2001-02-12 |
BR9813775A (en) | 2000-10-10 |
JP2001526217A (en) | 2001-12-18 |
HUP0100599A2 (en) | 2002-02-28 |
IL136518A0 (en) | 2001-06-14 |
EE200000394A (en) | 2001-12-17 |
SE9704770D0 (en) | 1997-12-19 |
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