Patent Application
20050032783
The present invention relates to a method of treatment or prevention of hot flushes in men who have undergone castration (castrated men), e.g. due to androgen ablation treatment in prostate cancer therapy (orchiectomy), comprising administration of an effective amount of a calcitonin gene-related peptide (CGRP) antagonist and/or of a CGRP release inhibitor to a person in need of such treatment. The method according to the invention preferably comprises monotherapy with a single substance, but also includes combined therapy with a number of substances from the specified groups of active substances.
In a second aspect, the invention relates to the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who have undergone castration.
Hot flushes and sweating, that is vasomotor symptoms, are reported by 43 to 77% of prostate cancer patients after medical or surgical castration, usually persisting for many years, possibly impairing quality of life (Arch. Surg. 43: 209, 1941; J. Urol. 152: 1170, 1994). Furthermore, hot flushes occur in 75% of women after menopause. In WO 01/10425 it has been proposed that the symptoms of menopausal hot flushes can be effectively prevented or their distressing effects substantially alleviated by substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP release inhibitors), this therapeutic approach being superior to hormone replacement therapy in particular because of its lack of side effects.
Although it has been already reported that plasma calcitonin gene-related peptide was increased during hot flushes in six men who underwent castration therapy, the mechanism of hot flushes in men is not well known. For instance, it is unclear up to now why some men have vasomotor symptoms whereas some do not and it was suggested to discover more about the mechanism of these symptoms to develop new treatment alternatives (J. Urol. 166: 1720-1723, 2001).
There is a clear need for alternative approaches and improvement in the treatment and prevention of hot flushes in men who have undergone castration.
It is therefore an object of the invention to provide a method of treatment and prevention of hot flushes in men who have undergone castration, comprising administering to a patient in need of such treatment an effective amount of a CGRP antagonist and/or of a CGRP release inhibitor.
A second object of the invention is the use of a CGRP antagonist and/or of a CGRP release inhibitor for manufacture of a pharmaceutical composition for prevention or treatment of hot flushes in men who have undergone castration.
It has now been found that the symptoms of hot flushes in men who have undergone castration can be effectively prevented or their distressing effects substantially alleviated by substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP release inhibitors), this therapeutic approach being superior to conventional therapy.
The present invention thus relates to the use of CGRP antagonists and/or CGRP release inhibitors for combating hot flushes in men who have undergone castration, including both prevention and acute treatment. The use according to the invention preferably comprises monotherapy with a single substance, but also includes combined therapy with a number of substances from the specified groups of active substances. Moreover, the treatment according to the invention may be carried out in addition to conventional therapy, thus any aspect of the invention includes combination with conventional therapy or those drugs used in conventional therapy.
The expression “conventional treatment” is meant to comprise:
Suggested recommendations for conventional treatment of hot flushes in men with prostate cancer treated by castration are:
First-line Treatments:
The invention also includes the use of an active substance selected from CGRP antagonists and CGRP release inhibitors for the preparation of a pharmaceutical composition for treatment or prevention of hot flushes in men who underwent castration wherein the pharmaceutical composition comprises an active compound used in conventional therapy selected from the group consisting of:
Any pharmaceutically acceptable active substances which antagonise the known effects of CGRP or inhibit the release of CGRP from sensory nerve endings may be used for the purposes of the present invention. Examples of CGRP antagonists include the amino acid derivatives described in WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 and WO 01/49676 as well as the non-peptidic active substances described in WO 98/56779, WO 98/09630 and WO 97/09046.
Examples of CGRP release inhibitors include serotonin 5-HT1B/1D-agonists such as almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, as well as 5-HT1F-agonists or NPY-agonists.
Of the CGRP antagonists described in WO 98/11128, the following compounds, for example, may be used for the treatment and/or prevention of hot flushes in men who underwent castration, or for the preparation of a corresponding pharmaceutical composition:
Preferred are the compounds:
Particularly preferred are the compounds:
The dosage required to produce the desired effect is about 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight for intravenous or subcutaneous administration and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight for administration by oral or nasal route or by inhalation, 1 to 3 times a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given as a supplement to conventional therapy, it is advisable to reduce the doses given above, and in this case the dosage may range from 1/5 of the lower limits specified above up to 1/1 of the upper limits specified above.
For this purpose, the CGRP antagonists and/or CGRP release inhibitors may be formulated with one or more conventional inert carriers and/or diluents, e.g. with corr starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosols or suppositories.
Preparations which are particularly suitable for the method of treatment or prevention according to the invention are those which contain one of the following active substances:
In the method according to the invention and in any of the formulations given above active substance (A) may also be used in the form of a physiologically acceptable salt, preferably in the form of the hydrochloride salt which is available by reaction of the free base with hydrochloric acid by conventional methods. Amounts are given based on the free base.
CGRP is released by sensory nerves, e.g. the trigeminal nerve which innervates part of the skin of the face. It has already been shown that stimulation of the trigeminal ganglion in humans leads to an increase in the CGRP plasma level and causes reddening of the face ([4]: P. J. Goadsby et al., Annals of Neurology, Vol. 23, No. 2, 1988, 193-196, ).
To demonstrate that hot flushes can be successfully treated using CGRP antagonists and CGRP release inhibitors, an increased release of endogenous CGRP was induced in marmosets by stimulating the trigeminal ganglion, leading to increased blood flow through the blood vessels of the skin. The efficacy of the following test substances was characterised by determining the dose administered i.v. which reduces by 50% the increased blood flow through the skin of the face which has been brought about by endogenous CGRP:
Marmosets of both sexes (300-400 g) are anaesthetised with pentobarbital (initially with 30 mg/kg, i.p., followed by infusion of 6 mg/kg/h, i.m.). The body temperature is maintained at 37° C. using a heating plate. Pancurmium is administered as a muscle relaxant (initially 1 mg/kg, 0.5 mg after each hour thereafter). The animal's head is secured in a stereotactical apparatus. After the skin on the head has been opened using a lengthwise incision, a small hole is drilled in the skull and a bipolar electrode (Rhodes SNES 100) is lowered into the trigeminal ganglion.
Locating the ganglion is made easier by the use of an X-ray which shows the bone structure of the skull. The petrous bone serves as a guide for placing the electrode (CCX-Digital X-ray apparatus). The position of the electrode in the ganglion is monitored at the end of each experiment. The stimulation parameters are:
The blood flow in the micro-vessels of the facial skin is determined by laser Doppler flow measurement using a PeriFlux Laser Doppler System.
The animals are exposed to 2 to 3 stimulation periods at intervals of 30 min in each case. The first stimulation serves as a reference value for the other stimulations. The test substances are administered i.v. 5 min before the 2nd and 3rd stimulation periods.
The Examples which follow describe pharmaceutical preparations which contain as active substance a CGRP antagonist or CGRP release inhibitor for use according to the invention, preferably one of the amino acid derivatives described in WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 or WO 01/49676, for example one of the above-mentioned active substances (A) or (B), most preferred is substance (A) hydrochloride.
Method of Preparation:
The active substance is ground to the particle size needed for inhalation. The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.
Method of Preparation:
The active substance and benzalkonium chloride are dissolved in water and packed in Respimat® cartridges.
Method of Preparation:
Active substance, sodium chloride and benzalkonium chloride are dissolved in water.
Method of Preparation:
The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.
Method of Preparation:
The active substance and the excipients are dissolved in water and transferred into a suitable container.
Preparation:
Dissolve the glycofurol and glucose in water for injections (Wfl); add human serum albumin; add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into ampoules under nitrogen gas.
Preparation:
Dissolve glucose and polysorbate in water for injections; dissolve active substance with heating or using ultrasound; make up to specified volume with Wfl; transfer into ampoules under inert gas.
Preparation:
Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); add human serum albumin; dissolve active substance with heating; make up to specified volume with Wfl; transfer into ampoules.
Preparation:
Dissolve mannitol in water for injections (Wfl); add salt-forming agent; dissolve active substance with heating; make up to specified volume with Wfl; transfer into vials; freeze-dry.
Preparation:
Dissolve polysorbate 80 and mannitol in water for injections (Wfl); transfer into ampoules.
Preparation:
Dissolve active substance in suitable solvent; transfer into vials; freeze-dry.
Preparation:
Dissolve polysorbate 80 and mannitol in water for injections (Wfl); transfer into ampoules.
Preparation:
Homogeneously mix the active substance, lactose and maize starch; granulate with an aqueous solution of Povidone; mix with magnesium stearate; press in a tablet press; weight of tablet 200 mg.
Preparation:
Homogeneously mix the active substance, maize starch and silica; mix with magnesium stearate; transfer mixture into size 3 hard gelatine capsules in a capsule filling machine.
Preparation:
Melt the hard fat at about 38° C.; homogeneously disperse the ground active substance in the molten hard fat; after cooling to about 35° C., pour into chilled moulds.
Preparation:
The active substance is dissolved in purified water; hydrochloric acid is added until the solution is clear; methyl and propyl PHB are added; the solution is made up to the specified volume with purified water; the solution is filtered sterile and transferred into a suitable container.
Preparation:
The active substance is dissolved in 1,2-propanediol; a hydroxyethyl-cellulose solution in purified water containing sorbic acid is prepared and added to the solution of active substance; the solution is filtered sterile and transferred into a suitable container.
Preparation:
The active substance is dissolved in 1,2-propanediol; the solution is made up to approximately the specified volume with Wfl; the mannitol is added and made up to approximately the specified volume with Wfl; the solution is filtered sterile, transferred into individual containers and autoclaved.
Preparation:
The active substance is dissolved in a mixture of lecithin and cholesterol; the solution is added to a mixture of glycerol and Wfl and homogenised by high pressure homogenisation or by the Microfluidizer technique; the liposomal formulation obtained is transferred into a suitable container under aseptic conditions.
Preparation:
The active substance is suspended in an aqueous CMC solution; the other ingredients are added successively to the suspension and the suspension is topped up to the specified volume with purified water.
Preparation:
The active substance is dissolved in the phosphate buffer solution, after the addition of the common salt the solution is made up to the specified volume with water. The solution is filtered sterile, transferred into a suitable container and autoclaved.
Preparation:
The active substance is suspended in the polysorbate 80 solution and comminuted to a particle size of about 1 μm using a suitable dispersing technique (e.g. wet grinding, high pressure homogenisation, microfluidisation, etc.). The suspension is transferred into a corresponding container under aseptic conditions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 03015335.7 | Jul 2003 | EP | regional |
| 03021802.8 | Sep 2003 | EP | regional |
This application claims priority benefit of U.S. application Ser. No. 60/491,576, filed Jul. 31, 2003, European Application No. 03 015 335.7, filed Jul. 7, 2003, U.S. application Ser. No. 60/515,817, filed Oct. 30, 2003, and European Application No. 03 021 802.8, filed Sep. 26, 2003, each of which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60491576 | Jul 2003 | US | |
| 60515817 | Oct 2003 | US |
