MEDICAMENTS FOR THE TREATMENT OF ANXIETY

Abstract: A method for the treatment and/or prophylaxis of anxiety in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist.

Description: MED1CAMENTS FOR THE TREATMENT OF ANXIETY This invention relates to a method of treatment of anxiety in mammals, including humans. European Journal of Pharmacology 146 (1988), 187-188, and Naunyn- Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT4 receptor. EP-A-501322 (Glaxo Group Limited), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham pic) describe compounds having 5-HT4 receptor antagonist activity. Some 5-HT3 receptor antagonists have been disclosed as of potential use in the treatment of anxiety (see GB 2153821A, EP-A-229444 (Glaxo Group Ltd.) and EP-A-201165 (Beecham Group p.l.c)). We have now discovered that a compound which acts as an antagonist at 5-HT4 receptors is of potential use in the treatment of anxiety, such as general anxiety disorder (GAD), mixed anxiety/depression or panic disorder. The conditions under which anxiolysis is observed for this compound in the elevated X-maze differs from those required for the observation of the anxiolytic effects of 5-HT3 receptor antagonists. Furthermore the site of action of 5-HT3 receptor antagonists is thought to be the amygdala (Higgins et al 1991, Pschopharmacology, 104, 545-551), while 5-HT4 receptor mediated anxiolysis is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). The invention therefore provides a method for the treatment and/or prophylaxis of anxiety in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist. 5-HT4 receptor antagonists may be identified according to standard methods, such as that described hereinafter, and the methods described in Naunyn-Schmiedeberg's Arch Pharmacol. 342, 619-622 and M 439-446, and J. Pharamcol. Exp. Ther. (1990) 252. 1378-1386.. Examples of 5-HT4 receptor antagonists include R 50595 (Janssen), which is described in FR76530 and EurJ. Pharmacol., lδl 119-125 (1990), SDZ 205-557, which is described by K.H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol., 242 (Supp ), R101 (1991) and 245, 387-393 (1992), DAU 6215 (Br. J. Pharmacol. (1991), 1-Q4, Proc. Supp.47P, DAU 6285 (Naunyn-Schmiedeberg's Arch. Pharmacol, 45; 264-269 (1992), RS 23597-190 (Syntex - British Pharmacology Society Meeting, September 1992), SC 53606 (Searle - 2nd International Symposium on Serotonin, Houston, USA , - September 1992) and GR113808 (Glaxo - EP -A- 501322). ICS 205-930 (tropisetron), which is described in GB 2125398A (Sandoz Limited) is also a 5-HT4 receptor antagonist, but is far more potent as a 5-HT3 receptor antagonist. In a preferred aspect, the 5-HT4 receptor antagonist is a more potent antagonist at 5-HT4 receptors than at 5-HT3 receptors. Preferably, the 5-HT4 receptor antagonist is in substantially pure pharmaceutically acceptable foim. The administration of the 5-HT4 receptor antagonist may be by way of oral, sublingual, transdermal or parenteral administration. An amount effective tp treat the disorder hereinbefore described depends on the usual factors such as the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the 5-HT4 receptor antagonist, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof. Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.1 to 5 mg, that is in the range of approximately 0.001 to 1 mg kg/day, more usually 0.005 to 0.2 mg kg day. For oral or parenteral administration, it is greatly preferred that the 5-HT4 receptor antagonist is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition. Such compositions are prepared by admixture and are suitably adapted for oral 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. Tablets and capsules for oral 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 or tabletting. Repeated blending operations may be used to distribute the active agent 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 the 5-HT4 receptor antagonist and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the 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 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 treatment concerned. The present invention also provides the use of a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of anxiety. Such treatment and/or prophylaxis may be carried out as hereinbefore described. The present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinbefore described. 5-HT | receptor antagonist activity Male guinea-pigs, weighing 250-400g were used. Longitudinal muscle-myenteric plexus preparations, approximately 3cm long, were obtained from the distal colon region. These were suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO2 in O2 and maintained at 37°C. In all experiments, the Krebs solution also contained methiothepin 10"^M, methysergide 2xl0"^M and granisetron 10"^M. After construction of a simple concentration-response curve with 5-HT, using 30s contact times and a 15min dosing cycle, a concentration of 5-HT is selected so as to obtain a contraction of the muscle approximately 40-70% maximum(10-9M approx). The tissue is then alternately dosed every 15min with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant (dimethylphenyl piperazinium) DMPP. After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, IC50 values are determined, being defined as the concentration of antagonist which reduced the contraction by 50%. A compound which reduced the response to 5-HT but not to DMPP is believed to act as a 5-HT4 receptor antagonist. In Nivo Testing Social Interation Rats (male, Sprague Dawleys, Charles River, 250-300g) are housed in groups of eight in a holding room for 5 days. They are then housed singly in a room adjacent to the experimental room for 4 days prior to the experimental day. On the experimental day rats are administered vehicle, test compound or a benzodiazepine anxiolytic, chlordiazepoxide, S.C. in pairs (n=8-16), at 15 minute intervals beginning at 10.00 am. 30 mins. later they are placed with a weight matched pair-mate (encountered for the first time) in the social interaction box in a separate room. The box is made of white perspex 54 cm x 37 cm x 26 cm with a transparent perspex front side and no lid. The floor is divided up into 24 squares and the box is brightly lit (115 lux). Active social interactive behaviours (grooming, sniffing, climbing over or under, following, biting, mounting and boxing) are scored blind for 15 min. by remote vido monitoring to give total interaction scores. The number of squares crossed by each rat is also scored and summed. After the end of each text the box is carefully wiped. X-Maze The X-maze is raised 50 cm above the floor and consists of two enclosed arms 45 cm (long) x 10 cm (wide) and 10 cm (high) and two open arms 45 x 10 x 1 cm, arranged such that the two arms of each type are opposite each other. Both arm types are marked into two equal sections. Rats are placed onto the centre of the X-maze and observed for a period of five min. during which time the following parameters are recorded: 1). The number of entries on to, and the time spent on, (a) open arms (b) closed arms, (c) end of open arms and (d) end of closed arms. 2) the number of sections crossed. The fear drive evoked in the open arms exceeds that in the closed arms and rats typically show a clear preference for the enclosed arms. Anxiolytic drugs increase the number of entries made onto, and the time spent on, the outer half of the open arms, and also the percentage of entries made onto, and the time spent on, the whole of the open arms. These four measures of anxiety, and also the total number of sections traversed, are calculated for each animal.

Claims: Claims 1. A method for the treatment and/or prophylaxis of anxiety in mammals, including humans, which method comprises administering to the mammal in need of such treatment and/or prophylaxis, an effective and/or prophylactic amount of a 5-HT4 receptor antagonist. 2. The use of a 5-HT4 receptor antagonist in the manufacture of a medicament for use in the treatment and/or prophylaxis of anxiety. 3. A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, which comprises a 5-HT4 receptor antagonist, and a pharmaceutically acceptable carrier. 4. A method, use or composition according to claim 1, 2 or 3 wherein the 5-HT4 receptor antagonist is more potent at 5-HT4 receptors than at 5-HT3 receptors. 5. A method, use or composition according to claim 4 for the treatment of general anxiety disorder (GAD) or mixed anxiety/depression. 6. A method, use or composition according to claim 5 for the treatment of panic disorder. 7. A method, use or composition according to claim 1, 2 or 3 wherein 5-HT4 receptor antagonist is R 50595, SDZ 205-557, DAU 6285, RS 23597-190, SC 53606 or GR 113808. 8. A method, use or composition according to claim 1, 2 or 3 wherein 5-HT4 receptor antagonist is a compound described in relation to WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham pic).

Inventors: BAXTER GORDON SMITH, KENNETT GUY ANTHONY, BAXTER, GORDON, SMITH, KENNETT, GUY, ANTHONY
Applicants: BAXTER GORDON SMITH, KENNETT GUY ANTHONY, SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25