EP0626849A1

EP0626849A1 - Brofaromine as an agent for treating post-traumatic stress

Info

Publication number: EP0626849A1
Application number: EP93903683A
Authority: EP
Inventors: Richard Katz
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1992-02-21
Filing date: 1993-01-27
Publication date: 1994-12-07
Also published as: KR950700063A; CA2117430A1; WO1993016695A1; JPH07503972A; AU3484493A; NZ249041A; AU676672B2

Abstract

L'invention concerne un procédé de traitement de troubles liés au stress post-traumatique chez un animal à sang chaud nécessitant ce traitement, et qui consiste à administrer audit animal une quantité efficace de brofaromine ou d'un sel pharmaceutiquement acceptable de celle-ci afin de traiter les troubles liés au stress post-traumatique.The invention relates to a method for treating post-traumatic stress disorder in a warm-blooded animal in need of this treatment, which comprises administering to said animal an effective amount of brofaromine or a pharmaceutically acceptable salt thereof in order to to treat post-traumatic stress disorder.

Description

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BROFAROMINE AS AN AGENT FOR TREAΗNG POST-TRAUMATIC STRESS

FIELD OF THE INVENTION

The present invention relates to psychological disorders associated with traumatic stress and its management. The invention further deals with brofaromine, a selective, reversible onoamine oxidase type A inhibitor, with serotonin uptake inhibitory properties..

BACKGROUND

Brofaromine is an Monoamine Oxidase (MAO) inhibitor antidepressant compound, first patented in the US in 1980 by Schenker et al. (US 4,210,655), which patent is incorporated herein by reference. This patent states that brofaromine, i.e. 4-(5-methoxy-2- benzofuranyl)-piperidine, is a selective MAO type A inhibitor, blocks serotonin reuptake, and that the compound is useful in the treatment of depression.

J. Neural Transm (1989) [Suppl] 28: 21-31 discusses the differences in effect on tyramine-elicited blood pressure elevation in subjects which were not medicated, medicated with irreversible MAO inhibitors, or reversible MAO inhibitors. Brofaromine and moclobemide are mentioned specifically as the reversible MAO inhibitors. There is no mention or suggestion of efficacy in psychological disorders of any kind.

J. Neural Transm (1989) [Suppl] 28: 33-44 reports on the therapeutic and side effect profile of brofaromine in the context of depressive disease states.

In recent years, it has become increasingly clear that there are a number of distinct psychological disorders that are not well understood and have been inappropriately lumped together in the past Many of these disorders can occur with or without depression as a component thereof. Separate and apart from depression, the following have now been recognized by DSM-ID.-R, the diagnostic and statistical manual of the American Psychiatric Association, as distinct disorders: panic disorder with agoraphobia, social phobia, bulimia, borderline personality disorder, and post-traumatic stress disorder (PTSD) among others.

PTSD is a condition believed to be brought on by the witnessing of traumatic events which so shock ones sensibilities that an indelible mark is left on the individual. Motor vehicle accidents, war injuries, crime (especially violent crime), child and spousal abuse, natural disasters, industrial accidents, etc. are typical types of incidents which carry some of the hallmarks of PTSD in susceptible patients whether or not there is any significant physical injury to the victim of or participant in the event More importantly, there is an even larger population of patients exhibiting the symptoms of the disorder who have merely witnessed the events, especially if the witnessed events are particularly horrifying.

The disorder is characterized by: reexperiencing of intrusive thoughts and images in waking and sleep, increased arousal and hypersensitivity to trauma-related stimulation, and persistent avoidance activity. According to the American Psychiatric Association DSM-IH-R criteria, PTSD is diagnosed when

1. the patient has experienced an event outside the range of usual human experience and that event would be distressing to almost everyone;

2. the patient has recurrent and intrusive distressing recollections or dreams of the event or feelings of the event recurring or psychological distress at exposure;

3. the patient persistently practices at least three avoidant behaviors such as making efforts to avoid thoughts or feelings, making efforts to avoid activities or situations, has psychogenic amnesia of the trauma, has lessened interest in significant activities, is detached or estranged, has a sense of foreshortened future, and a restricted range of affect;

4. the a patient has increased arousal evidenced by at least two of difficulty in falling or staying asleep, irritability or outbursts of anger, difficulty in concentrating, hypervigilence, and exaggerated startle response; and

5. the symptoms have persisted for at least one month.

Liebowitz et al, "Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders", Acta Psychiatr Scand 1990: Suppl 260: 29-34, summarize the studies showing that MAO inhibitors generally have some utility in treating these disorders. The authors conclude that the reversible MAO inhibitors, such as moclobemide, appear safer than the classical irreversible MAO inhibitors for these and other therapeutic applications generally ascribed to MAO inhibitors, if they are in fact found to be efficacious for those utilities. With specific reference to PTSD, the authors do not indicate that any reversible or selective MAO inhibitor has been studied. At page 32, Column 1, lines 7-8, the authors state that both the classical MAO inhibitors and the reversible MAO inhibitors need to be studied further in PTSD.

PTSD is a psychological disease state for which various treatments have been reviewed in Arch Gen Psychiatry, Vol 47, March 1990, pp 259-266; J. Clin Psychiatry 51:10 (suppl), pp 33-38, October 1990; and M. Friedman, "Biological Approaches to the Diagnosis and Treatment of Post-Traumatic Stress Disorder, J. Traumatic Stress 4(1), 67-91, 1991.

The Journal of Clinical Psychiatry article mentions the use of tricyclic antidepressants and MAO inhibitors generally in the treatment of PTSD. These are discussed at page 34, Column 2 through page 35, Column 2. The only MAO inhibitor discussed is phenelzine and the symptoms showing improvement fall into the intrusive recollections and hyperarousal areas. There is no mention of any effect on the avoidant behavior aspects of the condition. The Friedman article mentions that virtually every type of psychotropic agent appears to alleviate DSM-III-R intrusive recollections and hyperarousal, but does not alleviate the avoidant symptoms of the disorder. Brofaromine is not mentioned. Phenelzine is the only MAO inhibitor discussed and appears to be the only agent of this class tested in PTSD heretofore. The Arch Gen Psychiatry reference appears to be cumulative with the other two articles mentioned here.

In addition, recent reports suggest serotonin uptake inhibitors may benefitintrusive avoidant and hostile aspects of PTSD (Davidson, et al, J. Traumatic Stress 4(3), 419-425 (1991); Shay, J. Traumatic Stress 5(1), 97-103 (1992), each dealing with fluoxetine).

From the foregoing, it is clear that no agent to date has provided a suitable treatment for PTSD. The tricyclic antidepressants have only been of moderate success. Classical MAO inhibitors (irreversible inhibitors) have been seen to be more successful, but there use is severely limited by the pressor effects that could result from dietary and other sources of monoamines and the lack of confidence that patients with PTSD could or would adhere to appropriate self regulation of their monoamine intake. A drug combining MAO inhibitory and serotonin uptake inhibitory proprieties might be especially of benefit, and represent synergistic benefits upon more symptoms.

The major problem with the use of classical MAO inhibitors is that they have significant safety profile disadvantages, as noted above. Development of newer and better MAO inhibitors would therefore be likely candidates for testing in conditions for which the MAO inhibitors are known to be useful. With the discovery of the reversible MAO inhibitors moclobemide and brofaromine, this was a potential possibility. However, since the particular mechanism of action of classical MAO inhibitors is intimately tied to the reason for their poor safety profiles, one would not expect to obtain any improvement in the safety profile without a concomitant reduction in efficacy merely by having reversible MAO inhibitors.

Additionally, while the classical MAO inhibitors are nonselective and irreversible inhibitors of both type A and type B MAO, moclobemide and brofaromine are selective, inhibitors of type A MAO. As such, one would expect reduced efficacy as compared to the classical MAO inhibitors since with moclobemide and brofaromine, type B MAO is still available to act in its normal course. Moclobemide also has a potential safety problem similar to the classical MAO inhibitors since its metabolite is an MAO type B inhibitor. MAO type B is primarily responsible for removing tyramine.

OBJECTS OF THE INVENTION

It is therefore an object of the invention to provide a treatment for PTSD which overcomes the defects in the existing armamentum for treating PTSD as well as medicaments for the treatment of PTSD.

It is a further object of the invention to provide a PTSD treatment and or a medicament for the treatment of which can be administered without close supervision of the patient and thereby allow for greater outpatient treatment possibilities.

Another object of the invention is to provide a PTSD treatment and/or a medicament for the treatment of which will reduce or eliminate the avoidant behavior and hostile symptoms of the disorder.

SUMMARY OF THE INVENTION Surprisingly, these and other objects of the invention are achieved by treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment by administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The present invention is a method of treating post-traumatic stress disorder in a warm-blooded animal in need of such treatment comprising administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof. Brofaromine and its pharmaceutically acceptable salts are disclosed in US Patent 4,210,655, which is incorporated herein by reference. The cited patent also discloses the synthesis of brofaromine and its pharmaceutically acceptable salts, their uses in depression, their pharmaceutical compositions, antidepressant dosages, and routes of administration. All of this disclosure is applicable to the instant invention.

Especially prefenred salts of brofaromine for use in the instant invention include, without limitation, the salts formed from the combination of brofaromine with one of the acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, and embonic acid. Most preferably the salt is the hydrochloride.

Particularly advantageous dosage amounts and regimens (based on free brofaromine) are selected from about 0.1 to about 5.0 mg kg, more preferably about 0.5 to about 2.0 mg kg, most preferably about 1.0 to about 1.5 mg/kg, given from 1 to 4 times a day in single or divided doses, more preferably from 1 to 3 times a day, and typically given orally or by intravenous injection twice daily.

Preferred compositions of brofaromine contain 50 or 75 mg of brofaromine per dosage unit intended for mammals of 40 to 70 kg. In addition to brofaromine, the compositions typically contain generally acceptable pharmaceutical carriers, such as lactose, saccharose, sorbitol, and mannitol; starches, such as potato starch, corn starch, and amylopectin; cellulose derivatives; or gelatin. If desirable, the compositions may also contain a lubricant, such as magnesium stearate, calcium stearate, or polyethylene glycol. Other standard agents used in the manufacture of tablets, capsules, or intravenous solutions may also be present as appropriate.

The invention will be further clarified, but is not limited, by the following Examples, which are presented for exemplification purposes only.

Example 1: An adult individual having suffered acute sexual trauma and satisfies the DSM-III-R criteria for PTSD is given brofaromine hydrochloride (in an amount sufficient to administer 50 mg of free brofaromine) twice daily. The normally present psychological sequelae of the trauma, inclusive of images of the traumatic event, social and situational phobic avoidance and increased arousal to associated stimuli are all significantly reduced.

Example 3: An individual having witnessed military atrocities and satisfies the DSM-IH-R criteria for PTSD is given brofaromine hydrochloride (in an amount sufficient to administer 75 mg of free brofaromine) twice daily. Recollections of the trauma, social avoidance, social and vocational disability, and increased arousal to associated stimuli are all substantially reduced.

Example 3: Tablets, each comprising 50 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)- piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows:

Composition (10 000 tablets)

active ingredient 500.0 g lactose 1000.0 g potato starch 852.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.

The active ingredient is mixed with the lactose and 792 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remaining potato starch, the magnesium stearate, the talc and the silica are mixed in and the mixture is compressed to form tablets which each weigh 295.0 mg and comprise 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adjustment of the dose.

Example 4: Film-coated tablets, each comprising 50 mg of 4-(7-bromo-5-methoxybenzo- furan-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared . as follows:

Composition (for 1000 film-coated tablets)

active ingredient 50.0 g lactose 200.0 g com starch 120.0 g talc 17.0 g calcium stearate 10.0 g hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s. methylene chloride q.s.

The active ingredient, the lactose and 90 g of the com starch are mixed, and the mixture is moistened with a paste, prepared from 30 g of com starch and water (with heating), and granulated. The granules arc dried, and the remaining com starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 400 mg), which are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of each film-coated tablet: 583 mg.

Example 5: Hard gelatin capsules, each containing 500 mg of 4-(7-bromo-5-methoxy- benzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared, for example, as follows:

Composition (for 1000 capsules)

active ingredient 500.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium Iauryl sulfate 2.0 g magnesium stearate 8.0 g

The sodium Iauryl sulfate is added to the lyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are mixed intimately. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and then the micro- crystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is mixed intimately again for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, hard gelatin capsules of a suitable size are each filled with 790 mg of the resulting formulation.

Example 6: A 5 % injection or infusion solution of 4-(7-bromo-5-methoxybenzofuran-2- yl)piperidine or of a salt, for example the hydrochloride, thereof can be prepared, for example, as follows:

Composition (for 1000 or 400 ampoules)

active ingredient 125.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g demineralised water ad 2500.0 ml

The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added, and the mixture is made up to 2500 ml with water. To prepare unit dose forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 50 or 125 mg, respectively, of active ingredient.

Claims

What is claimed is:

1. A method of treating post-traumatic stress disorder in a warm-blooded animal in need

« of such treatment comprising administering to said animal a post-traumatic stress disorder treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said warm-blooded animal is a human being.

3. The method of claim 1 wherein said effective amount, based on free brofaromine, is from about 0.1 mg/kg to about 5.0 mg/kg.

4. The method of claim 1 wherein said pharmaceutically acceptable salt of brofaromine is the hydrochloride salt

5. The method of claim 1 wherein said administering is via the oral or intravenous route.

6. The method of claim 1 wherein said brofaromine or pharmaceutically acceptable salt thereof is administered in a composition comprising in addition to said brofaromine or salt thereof, a pharmaceutically acceptable carrier.

7. The method of claim 1 wherein said brofaromine or salt thereof is administered orally in a tablet or capsule.

8. A pharmaceutical composition for treating treating post-traumatic stress disorder, containing a social phobia treating effective amount of brofaromine or a pharmaceutically acceptable salt thereof in admixture to conventional pharmaceutical auxiliarie.

9. A pharmaceutical composition as claimed in claim 8 wherein said effective amount, based on free brofaromine, is from about 0. 1 mg kg to about 5. 0 mg kg.

10. A pharmaceutical composition as claimed in claim 8 in the form of a tablet or capsule or of an injectionable solution containing 25 to 100 mg of brofaromine as hydrochloride salt.