WO1999022723A1

WO1999022723A1 - Epi-inositol compositions for the treatment of cns disorders

Info

Publication number: WO1999022723A1
Application number: PCT/IL1998/000523
Authority: WO
Inventors: Robert Haim Belmaker
Original assignee: Ben-Gurion University Of The Negev
Priority date: 1997-10-30
Filing date: 1998-10-29
Publication date: 1999-05-14
Also published as: IL122077A0

Abstract

A pharmaceutical composition, comprising as an active ingredient a CNS effective amount of epi-inositol.

Description

EPI-INOSITOL COMPOSITIONS FOR THE TREATMENT OF CNS

DISORDERS

Field of the Invention

The present invention relates to the preparation of, and to a method for use of, the synthetic compound epi-inositol in CNS-related disorders.

Background of the Invention

Myo-Inositol is a naturally occurring isomer of glucose that serves as a

precursor in the phosphatidylinositol (PI) cycle which generates the second

messengers diacylglycerol (DAG) which activates protein kinase C, and

inositol triphosphate (IP3) which enhances intracellular calcium flow.

Chronic myo-inositol treatment was reported to reduce anxiety levels in

rodents (Cohen H, Kotler M, Kaplan Z, Matar MA, Kofman O, Belmaker RH

(1997), J Neural Transm 104: 299-305), and to have a therapeutic effect in

human patients suffering from panic disorder and agoraphobia (Benjamin J,

Levine J, Fux M, Aviv A, Levy D, Belmaker RH (1995), Am. J. Psychiatry,

152: 1084-1086). These effects may be the result of the linkage between the

serotoninergic system and PI cycle- derived second messengers (Snider RH,

Fisher SK, Agranoff BW (1987) "Inositide-linked second messengers in the

central nervous system". In: Meltzer HY (ed) Psychopharmacology: The

third generation of process. New York: Raven Press). Myo-inositol also has .

therapeutic effects in depression and in obsessive-compulsive disorders. Epi-inositol is an artificial stereoisomer of myo-inositol, which has

previously been considered inactive in biological systems (Benjamins JA,

Agranoff BW (1969), J. Neurochem 16: 513-627).

It has now surprisingly been found, and this is an object of the present invention, that epi-inositol, a synthetic isomer of myo-inositol, is active against Central Nervous System (CNS) disorders. It has further been surprisingly found that epi-inositol is more effective than its naturally-occurring stereoisomer, myo-inositol, e.g., as an antidepressant and in reducing anxiety levels.

It has further been found, and this is another object of the invention, that epi-inositol can be effectively used in smaller amounts than its naturally-occurring stereoisomer, myo-inositol, as a CNS drug.

It is another object of the invention to provide CNS drugs comprising epi-inositol as an effective pharmaceutical agent, alone or in admixture with other CNS or other drugs. Epi-inositol can be effectively used, e.g., in antidepressant compositions, anxiolytic compositions, anti-panic compositions or compositions for the treatment of obsessive-compulsive disorders.

It is still another object of the invention to provide a method for reducing anxiety levels and depression, comprising administering to a subject in need thereof an anxiety and depression-reducing effective amount of a composition comprising epi-inositol as the active ingredient. Summary of the Invention

In one aspect, the invention is directed to a pharmaceutical composition, comprising as an active ingredient a CNS (Central Nervous System) effective amount of epi-inositol. By CNS-effective amount it is meant to indicate an amount of epi-inositol which is beneficially active on the Central nervous System and, thus, influences CNS disorders such as depression, anxiety, panic, etc.

According to a preferred embodiment of the invention, epi-inositol is used as the active ingredient in pharmaceutical compositions useful for treating a variety of disorders, including but not limited to antidepressant compositions, anxiolytic compositions, anti-panic compositions and composition for the treatment of obsessive-compulsive disorder.

Such pharmaceutical compositions may, of course, further comprise pharmaceutically acceptable carriers and/or additives.

The pharmaceutical compositions of the invention may be provided in different forms, e.g., in orally administerable form, such as in tablet, capsule or liquid form. Epi-inositol powder may be dissolved in orally palatable form, e.g., as a drink, or made into tablets or capsules. A typical dosage form of epi-inositol tablets or capsules will contain 500 mg, although other dosage forms can of course be used. The invention further encompasses the use of epi-inositol as an active ingredient in CNS drugs. Furthermore, the invention in another aspect relates to epi-inositol, for use in the preparation of a drug.

The compositions of the invention are useful in a method of treating a patient suffering from a CNS disorder, comprising administering to said patient a pharmaceutically-effective amount of epi-inositol.

All the above and other characteristics and advantages of the invention will be further understood through the following illustrative and non-limitative description of specific examples thereof.

Brief Description of the Drawings

Fig. 1: Shows the performance of groups in the plus-maze test:

- Fig. 1A is the time spent in open arms;

- Fig. IB is the number of entries to open arms;

- Fig. 1C is the ratio of time spent in open/ closed arms; and

- Fig. ID is the ratio on number of entries to open/ close arms.

An asterisks (*) signifies significant difference from the control group, and a plus (+) signifies significant difference from the myo-inositol group. Significance level was set at p< 0.05. Detailed Description of the Invention

Example 1

Twenty seven adult male Sprague-Dawley rats, weighing 200-250 gm at the

beginning of the experiment served as subjects. Rats were housed 4 per

cage in a temperature controlled (22°C) colony room, with a 12 hr. light/

dark cycle, and with free access to food and water. To reduce stress

associated with the experimental procedure, rats were handled by the

experimenter for a week prior to the beginning of experiment, 2 minutes

every day. All experimental and test procedures were performed during the

later part of the light phase.

Myo-inositol (N=9), Epi-inositol (N=9), and control solution (N=9; 3:1

mannitol/ glucose) at a dose of 1.25 gm/kg were injected I.P at a volume of

12.5 ml/kg. once a day for 11 days. All injection solutions were diluted to

10% in saline. Treatment dose and schedule were chosen because with

myo-inositol they were shown to reduce anxiety in the elevated plus maze

(Cohen et al., 1997, ibid). Myo-inositol, glucose and mannitol were obtained

from SIGMA (Israel). Epi-inositol was synthesised from myo-inositol and

was found to be pure by melting point and by chromatography. The

synthesis of epi-inositol from myo-inositol is known in the art and is

described, for example, in "The Cyclitols", Theodore Posternak, Holden-Day,

Inc., San Francisco, Cal, U.S.A., pp. 42, 94-95. Six to eight hours after the last injection animals were tested in an elevated

plus-maze. The maze was designed of 4 black perspex arms, each 50 cm

long, with a central platform of 10 x 10 cm. Two opposing arms had walls,

whereas the other two were open. The entire maze was elevated 50 cm from

ground. For behavioral testing, rats ware placed individually on the central

platform, facing different arms of the maze in a random order, and were

observed for 6 minutes sessions. An observer, blind to the treatment, scored

each rat's behavior, and sessions were also videotaped for later ratings.

Manual ratings included (1) Time spent in open arms of the maze, (2)

Number of entries to the open arms, and (3) ) Number of entries to the close

arms. Rating of videotapes included all of the above and also (4) Time spent

in the closed arms, and (5) Time spent on the platform. Rats are afraid to

enter the open, uncovered arms and do so only occasionally out of hunger or

curiosity. All anti-anxiety agents increase the number of entries and

amount of time in the open arms, and decrease the number of entries and

time in the closed arms. A detailed discussion of the elevated plus maze test

is found in File SE, Behaυ. Brain Res. 58(1-2): 199-202, 1993.

Data for the time measures was analyzed utilizing an ANOVA (analysis of

variance) statistics with planned comparisons between all groups. Since

variance for the computed measure of "Open/ close time ratio" was not

homogeneous (Levene's test, p<0.001), a square root transformation was performed after which homogeneity was corrected (Levene's test, p>0.89).

level of significance for all comparisons was set at p=0.05.

Results obtained from the video tapes scoring demonstrated that

experimental and control were not significantly different in the total

number of entries to all arms (ANOVA, F(2)=0.96, p>0.39). This comparison

may indicate that there was no apparent effect of treatment on levels of

activity.

Rats treated chronically with myo-inositol showed decreased anxiety

compared with control animals. The difference from the control group was

significant in measures of "Time spent in open arms" (F(l)=6.0546,

p<0.022; Fig. 1A), "Number of entries to open arms" (F(l)=5.3571; p<0.03;

Fig. IB), and "Open/ close time ratio" (F(l)=5.7748, p<0.025; Fig. 1C). A

non-significant trend is also demonstrated for "Open/ close entry ratio"

(F(l)=2.7763, p=0.1087; Fig. ID). However, no difference was shown in

measures of "Time spent in close arms" and "Time spent on platform" (data

not shown).

Rats treated repeatedly with epi-inositol also demonstrated lower amounts

of anxiety compared with control animals. Differences were significant for

"Time spent in open arms" F(l)=33.1615, p<0.001; Fig. 1A, "Number of

entries to open arms" F(l)=18.6667, p<0.001; Fig. IB, "Open/ close time ratio" F(l)=33.766, p<0.001; Fig. 1C, "Open/ close entry ratio" F(l)=14.482,

p<0.001; Fig. ID, and "Time spent in closed arms F(l)=14.894, p<0.001;

(data not shown). No difference was evident in the "Time spent on platform"

measure.

Furthermore, epi-inositol treatment had a significantly stronger effect than

myo-inositol in 4 measures: "Time spent in open arms" (F(l)=10.8767,

p=0.003; Fig. 1A), "Time spent in closed arms" (F(l)=13.475, p<0.002; data

not shown), "Open/ close time ratio" (F(l)=11.613, p<0.003; Fig. 1C), and

"Open/ close entry ratio" (F(l)=4.5768, p<0.043; Fig. ID). A similar trend

was demonstrated the "Number of entries to open arms" measure

(F(l)=4.02381, p=0.0563; Fig. IB).

Analysis of the manual score of "Time spent in open arms", and "Open/ close

entry ratio" was similar to the results obtained from the video tapes (data

not shown).

Preparation A

A tablet was prepared as follows: 500 mg of epi-inositol were admixed with

conventional binders prior to pressing. The tablet was lightly pressed in a

hand press. The table so prepared is ready for use. Preparation B

A capsule was prepared as follows: a gelatin capsule was filled with 500 mg

of epi-inositol. The capsule after sealing is ready for use.

Preparation C

A solution was prepared as follows: A saline solution was flavored with

lemon flavor. To the flavored solution there were added 3 gr of epi-inositol to

each 50 ml of solution. The resulting solution is a ready to be administered

orally.

The results provided above show that epi-inositol, an isomer of myo-inositol

reported not to be substrate for the enzyme PI synthase (Benjamins and

Agranoff, ibid; Williames MB, Jope RS (1995), Brain Res 685: 169-178), also

has an anxiolytic effect that may even be stronger than that of myo-inositol.

Since the obvious theory of myo-inositol's mechanism of action is that it acts

as a substrate for the enzyme PI synthase and therefore affects the level of

inositol phospholipids (PIP and PIP2), it will be appreciated that the fact

that epi-inositol which, as said, does not act as a substrate for the enzyme

PI synthase, is not only active in the same way as myo-inositol, but is

actually a more potent drug, is indeed very surprising. All the above description and examples have been provided for the purpose

of illustration and are not intended to limit the invention in any way. Many

modifications can be effected in the various compositions employed, both in

the administration route and in their contents, and different CNS disorders

may be treated using epi-inositol, all without exceeding the scope of the

invention.

Claims

CLAIMS:

1. A pharmaceutical composition, comprising as an active ingredient a CNS effective amount of epi-inositol.

2. An antidepressant composition, comprising as an active ingredient an antidepressant effective amount of epi-inositol.

3. An anxiolytic composition, comprising as an active ingredient an anxiolytic effective amount of epi-inositol.

4. An antipanic composition, comprising as an active ingredient an antipanic effective amount of epi-inositol.

5. A pharmaceutical composition for the treatment of obsessive- compulsive disorder, comprising as an active ingredient an effective amount of epi-inositol.

6. A composition according to any one of claims 1 to 5, further comprising pharmaceutically acceptable carriers and/or additives.

7. A composition according to claim 6, in orally administerable form.

8. A composition according to claim 7 in tablet form.

9. A composition according to claim 7 in capsule form.

10. A composition according to claim 7 in liquid form.

11. The use of epi-inositol as an active ingredient in a CNS drug.

12. Epi-inositol, for use in the preparation of a CNS drug.

13. A method of treating a patient suffering from a CNS disorder, comprising administering to said patient a pharmaceutically-effective amount of epi-inositol.