HK1004523B - Use of 5-ht1a agonists for the manufacture of a medicament protecting against ischaemic damage - Google Patents

Description

The present invention relates to to the use of a 5-HT1_A agonist.

EP-0041488 discloses 8-hydroxy-2-(di-n-propylamino) tetralin and a process by which it can be prepared. This compound, is described in the patent as a 5-HT-receptor agonist of potential use in the therapy of CNS disorders, in particular depression, and of sexual disturbances.

It has now been discovered that the compound has neuroprotectant activity. 8-Hydroxy-2-(di-n-propylamino) tetralin is therefore useful in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events, including cerebral ischaemia after cardiac arrest, stroke and multi-infarct dementia and also after cerebral ischaemic events such as those resulting from surgery and/or during childbirth.

Accordingly, the present invention provides the use of a 5-HT1_A agonist for the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals, such as humans.

Suitably, the 5-HT1_A agonist is a full 5-HT1_A agonist.

Preferably, the 5-HT1_A agonist is 8-hydroxy-2-(di-n-propylamino)tetralin, or a pharmaceutically acceptable salt thereof.

Suitable ischaemic events include cerebral ischaemia after cardiac arrest, stroke and multi-infarct dementia.

Further suitable ischaemic events include cerebral ischaemia which may result from surgery.

Also to be mentioned is the cerebral ischaemia which may occur in newborns during birth.

The administration to the mammal may be by way of oral, sub-lingual or parenteral administration as appropriate.

An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 50 mg such as 2, 5, 10, 20, 30, 40 or 50 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 50 to 250 mg,that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 1 to 4 mg/kg/day, for example 0.7 to 2 mg/kg/day.

It is greatly preferred that the active compound is administered in the form of a unit-dose composition, such as a unit dose oral, sub-lingual or parenteral composition.

Such compositions are prepared by admixture and are suitably adapted for oral, sub-lingual or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral and sub-lingual administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods of blending, filling and tabletting. Repeated blending operations may be used to distribute the active compound throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are prepared containing an active compound of the present invention and a sterile vehicle. The active compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

As used herein the terms "pharmaceutical composition" and "pharmaceutically acceptable" embrace compositions and ingredients for both human and veterinary use.

When used herein the term '5HT1_A agonist' relates to a compound which binds to a 5HT1_A receptor and ellicits a biological response.

When used herein the term 'full 5HT1_A agonist' relates to a compound being substantially free from 5HT1_A antagonist activity.

When used herein the term '5HT1_A antagonist activity' relates to a compound which binds to a 5HT1_A receptor and acts to block the biological response.

Examples of pharmaceutically acceptable salts of the compound include the hydrobromide.

In a further aspect the invention provides the use of a 5-HT1_A agonist for the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals, such as humans.

Such composition (medicament) may be prepared in the manner as hereinbefore described.

The following pharmacological data illustrate the neuroprotectant activity of the active compound in tests which are indicative of compounds of potential use in the treatment of the invention.

Pharmacological data Delayed neuronal death in gerbils after transient forebrain ischaemia. Method A

Ischaemia-induced nerve cell degeneration was produced in adult male gerbils by occlusion of both common carotid arteries for 3 minutes under halothane/nitrous oxide anaesthesia. Brains were removed 1 week later and 7µm thick coronal slices were examined light microscopically for neuronal degeneration.

3 groups of animals were used

• 1. sham ligated controls
• 2. solvent-treated ligated controls
• 3. compound-treated ligated animals

The test compound 8-hydroxy-2-(di-n-propylamino) tetralin (HBr salt) was administered intraperitoneally as an aqueous solution either 1 hour before or 1 hour after the start of the ligation period.

Method B

In an alternative procedure, the animals were placed upon a warming blanket during the carotoid artery occlusion, to avoid a drop in body temperature. The brains were then removed 2 weeks later and 12µm thick coronal slices were examined light microscopically for neuronal degeneration.

The remaining procedure was identical to that described in Method A.

Results:

means ± SEM (n) of a histopathological score which reflects the degree of neuronal damage in the hippocampal CA1 field:

0 =

no damaged neurons,

1 =

mild necrosis,

2 =

moderate necrosis,

3 =

severe necrosis,

4 =

complete necrosis.

In addition, the percentage of healthy animals is specified.

Method A	Sham ligated controls	Solvent treated ligated controls	Ligated animals treated with active compound
			10 mg/kg test compound i.p.
			1h preligation	1h postligation
Histopathological score (artificial units)	0* (4)	2.1±0.2 (55)	0*±0 (6)	0.7*±0.2 (18)
Healthy animals (%)	100*	25	100*	56*

*Significantly (p<0.05) different from solvent treated ligated controls.

Method B	Sham ligated controls	Solvent treated ligated controls	ligated animals treated with active compound
			1 mg/kg	10 mg/kg
			1h preligation	1h postligation
Histopathological score (artificial units)	0* (4)	3.4±0.1 (48)	1.3*±0.5 (7)	1.8*±0.6 (8)
Healthy animals (%)	100*	2	14	13

*Significantly (p<0.05) different from solvent treated ligated controls.

Claims (10)

1. The use of a 5-HT1_A agonist for the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals.
2. A use according to claim 1, wherein the 5-HT1_A agonist is a full 5-HT1_A agonist.
3. A use according to claim 1 or claim 2, wherein the 5-HT1_A agonist is 8-hydroxy-2-(di-n-propylamino) tetralin, or a pharmaceutically acceptable salt thereof.
4. A use according to any one of claims 1 to 3, wherein the ischaemic event includes cerebral ischaemia after cardiac arrest, stroke and multi-infarct dementia.
5. A use according to any one of claims 1 to 3, wherein the ischaemic event includes cerebral ischaemia resulting from surgery or that which may occur in newborns during birth.
6. A use according to any one of claims 1 to 4, wherein the medicament is a unit dose composition.
7. A use according to any one of claims 1 to 6, wherein the unit dose comprises from 1 to 500 mg of the agonist.
8. A use according to any one of claims 1 to 7, wherein the unit dose comprises from 2 to 50 mg of the agonist.
9. A use according to any one of claims 1 to 8, wherein the medicament is a parenteral composition.
10. A use according to any one of claims 1 to 9, wherein the medicament is an oral composition.