WO2003015804A1 - Treatment to improve central nervous system function - Google Patents

Abstract

Cereal plant extract (preferably from Secale Cereale or 'rye grass') for the improvement, enhancement or normalisation of central nervous system (CNS) functions including cognitive enhancement or stimulation, and for the treatment of CNS disorders, including anxiety and epilepsy.

Description

TREATMENT TO IMPROVE CENTRAL NERVOUS SYSTEM FUNCTION

FIELD OF INVENTION

This invention relates to substances and the use thereof for medicinal treatment to

improve or enhance or normalise central nervous system function and to treat central

nervous system disorders.

BACKGROUND ART

A number of mental disorders are caused by impaired central nervous system

function. Many drugs have been identified which effect the central nervous system (CNS).

The effects of psychopharmaceuticals were extensively studied by Fink et al, (1969), and

led to the division of psychopharmaceuticals into four classes (neuroleptics,

antidepressants, tranquillisers and psychostimulants). Neuroleptics such as the

benzodiazepines may be prescribed to treat conditions such as nervousness or tension as well as insomnia caused by anxiety; epilepsy; panic disorder or agoraphobia with panic

attacks. The disadvantage with the use of benzodiazepines is that they can have significant

adverse side effects and adverse reactions and should only be used for short periods of time.

Epilepsy is a common disorder characterised by sudden and recurrent disturbances in

mental function, state of consciousness, sensory activity, or movements of the body, caused

by paroxysmal malfunction of cerebral nerve cells. Epilepsy includes generalised

convulsions in which there is sudden unconsciousness with falling and shaking of limbs

("grand mal"), momentary lapses of awareness ("petit mal"), and local movements and sensations in parts of the body ("focal seizure"), as well as other types of activity that may include bizarre automatic behaviour, strange memories, illusory and hallucinatory

experiences, and changes in mood. The terms "cerebral seizure" and "convulsive disorder" are synonymous of epilepsy. Some of the causes of epileptic seizures can be treated; these include brain tumours,

infections, metabolic and endocrine abnormalities, and the formation of epileptogenic brain

tissue as a result of trauma. Surgical removal of epileptiform brain tissue is indicated in a

limited number of individuals, particularly those in whom the lesions are contained in a

single, surgically accessible area. In most epileptic individuals, however, the brain damage

cannot be reversed, and the control of seizures will depend on attempts at prevention of

attacks by medicinal means and the handling of problems of social adjustment. A treatment

that can be effective involves use of anticonvulsant medication, but long term treatment

with medication is needed.

An active substance as defined hereafter in relation to the present invention has been

described in Australian patent specification No. AU 81985/87 (patent No. 599725) by the

present applicant. In this prior patent specification, a range of possible uses of the

substance are described or indicated in passing. This earlier patent specification and

subsequent uses of the commercial product produced according to the prior patent specification have resulted in recognition of a range of physiological indications including

anti-inflammatory, immuno modulatory and analgesic activity. However, that prior

specification made no material reference or any suggestion concerning neurological

indications which might be useful in the treatment of CNS disorders or to improve or

enhance normalisation of CNS function.

It is an object of the present invention to provide uses, methods and products for treating CNS disorders (including symptoms), including anxiety and related disorders and epilepsy, or for improving or enhancing or normalising CNS function, including enhancing and stimulating cognitive function and in relation to subjects suffering from disorders including anxiety and related disorders and epilepsy. It is an object of the present invention to provide methods and products for treating

CNS disorders or for improving or enhancing or normalising CNS function.

It will be understood that discussion herein of treatments of central nervous system

disorders is intended to include reference to treatments to improve, enhance or normalise

central nervous system function unless the context requires otherwise.

SUMMARY OF INVENTION

According to the present invention there is provided a method of treating an animal,

including a human, having a central nervous system disorder comprising administering to

the animal a pharmacologically or therapeutically effective amount of an extract from cereal

plants, the extract including a pharmaceutically acceptable extract derived from juice of

cereal plants, the extract being carried in a pharmaceutically acceptable base carrier or

excipient.

According to another aspect of the invention there is provided a method of treating an

animal, including a human, having a central nervous system disorder selected from a group of disorders including epilepsy, the method including administering to the animal a

pharmacologically or therapeutically effective amount of an extract from cereal plants, the

extract including a pharmaceutically acceptable extract derived from juice of cereal plants,

the extract being carried in a pharmaceutically acceptable base carrier or excipient.

According to the present invention there is also provided a method of improving or

enhancing or normalising CNS function of an animal, including a human, in need thereof

comprising administering to the animal a pharmacologically acceptable extract derived from juice of cereal plants, the extract being carried in a pharmaceutically acceptable base, carrier or excipient. According to the present invention there is also provided a method of improving or

enhancing or normalising CNS function of an animal, including a human, in need thereof

including one having epilepsy comprising administering to said animal a pharmacologically

acceptable extract derived from juice of cereal plants, the extract being carried in a

pharmaceutically acceptable base, carrier or excipient.

The substance, which is to be administered in the methods of the present invention

and is described in the aforementioned Australian patent No. 599725, includes a

pharmaceutically acceptable liquid extract from a juice derived from cereal plants (which

includes wild grasses) and carried in a pharmaceutically acceptable carrier or excipient for

application to and take up by an animal subject. Such a substance will be referred to in the

present specification as "the active substance".

According to one aspect of the invention there is provided a pharmacologically or

therapeutically effective composition for the treatment of a central nervous system disorder,

said composition including a pharmacologically or therapeutically effective amount of an

extract from one or more cereal plants, said extract including a pharmaceutically acceptable

extract derived from juice of said cereal plant or plants, together with a pharmaceutically

acceptable carrier or excipient therefor.

According to another aspect of the present invention there is provided a product for

the treatment of central nervous system disorders or for improvement in or enhancement of

or normalisation of CNS function for the treatment of animals, including humans, the product including an active substance as defined above.

According to another aspect of the present invention there is provided a product for

the treatment of animals, including humans, having central nervous system disorders or

symptoms thereof including epilepsy, or for improvement in or enhancement of or normalisation of CNS function in epileptic subjects, the product including an active

substance as defined above.

In a further embodiment of the invention, there is provided the use of an active

substance as defined above for the manufacture of a product for the treatment of CNS

disorders or for improvement in or enhancement of or normalisation of CNS function of

animals, including humans.

In particular, the the enhancement of CNS function obtained by administration of the

inventive composition, product or extract may include cognitive enhancement or cognitive

stimulation.

In a further embodiment of the invention, there is provided the use of an active

substance as defined above for the manufacture of a product for the treatment of CNS disorders including epilepsy or for improvement in or enhancement of or normalisation of

CNS function of animals, including humans, having epilepsy.

The present invention in its more specific aspects therefore includes:

(a) methods of treating animals, including humans, having CNS disorders including

anxiety and related disorders and epilepsy or at least types of epilepsy susceptible of

treatment by the product of the present invention,

(b) methods of improving or enhancing or normalising CNS function of animals,

including humans, having CNS disorders including anxiety and related disorders and

epilepsy or susceptible types thereof,

(c) products for the treatment, improvement, enhancement or normalisation of CNS function in patients including patients suffering from epilepsy, and (d) the uses of an active substance (as defined herein) for manufacture of products for the

treatment, improvement, enhancement or normalisation of CNS function in patients

including patients suffering from epilepsy.

Reference may be made to the aforementioned AU-81985/87 for further background

and description of a substance of the kind described as useable in the present invention in its various aspects. However, the activity of the active substance of the kind defined above

in the treatment of CNS disorders, including anxiety and related disorders and epilepsy, or

improvement in or normalisation of CNS functioning is totally unexpected and surprising.

It has led to novel new uses of the active substance hitherto unknown and with no reason to

expect or suspect or seek such new uses.

References herein to "cereal plants" is to be interpreted to include wild grasses.

However, a particular cereal plant found to be particularly useful as a source of the extract

is Secale Cereale or "rye grass".

Extracts from barley and wheat are also believed to be effective. The wheat may

comprise Triticum vulgare or aestivum, T. durum, T. compactum, or triticale. Corn, rice,

oats, maize, sorghum and millet may also be effective.

Preferably the extract is derived from the green leafy part of the plant, or at least

principally from this part of the plant, although additional green parts such as stalk may be

included. The leaves of the plant are preferably treated to yield the extract before the plant

reaches flowering or seed production stage of development. That is, the plant is at its

unjointed or immature development stage.

The extraction is preferably carried out by squeezing, crushing and/or grinding

processes, not by a cutting process. Preferably the extract from the cereal plants comprises substantially only the water

soluble components of the juice.

The plant extract may be used in the concentration in which it is derived from the

plants. Alternatively, if desired, the extract may be concentrated and some or substantially

all the liquid content of the plant extract may be removed. For example, the extracted plant

matter may be dried, such as by spray drying to yield a powder for mixing with the carrier.

The spray drying is preferably carried out at a temperature of about 50°C and preferably

below 60°C.

Other possible stabilisation processes for the juice include partial concentration of the

derived juice to provide a concentrated liquid, freeze drying of the derived juice, and

blending the derived juice with a preserving agent forming an ingredient of the carrier.

Preferably the stabilisation or mixing with the carrier or both is carried out within a

short time and preferably within two hours after extraction.

h an alternative possibility the extract may be produced by firstly drying plant matter

after which the dried material is comminuted to yield a powder which includes ingredients originally in the juice.

The carrier for the extract may be any suitable material such as a liquid (e.g. water or

other solvent), cream, lotion, oil, gel or powder. For example the carrier may comprise a

liquid in which the extract is dissolved or vanishing cream which is intended to be absorbed

through the skin when applied so as to thereby carry the plant extract into sub-cutaneous

tissue. A water based or aqueous carrier capable of carrying water soluble ingredients to sub-surface tissues is preferred. Benzyl alcohol is a suitable carrier component for transdermal take up of the active ingredients. Preferably the carrier includes an anti-microbial agent so as to kill or at least inhibit

growth, reproduction or activity of contaminating organisms that may be present in the

plant extract or may be introduced during production of the substance. Preferably the

anti-microbial agent is an anti-bacterial agent. In addition or alternatively the agent may

have anti-fungal and anti-yeast properties. The anti-microbial agent may be added to the

substance during production or may be present in the carrier if the carrier for example is a

standard commercially available product. The anti-microbial agent is preferably active to

inhibit any activity of organisms and thereby is operative to inhibit spoilage of the

substance, e.g. spoilage of the product when being stored by the user or by a commercial

outlet.

If the anti-microbial is not provided, it is preferred that the extract is substantially

sterile when mixed with the carrier. The plants from which the extract is derived may be

grown hydroponically for example under sterile conditions to prevent the introduction of

micro-organisms at that stage. The subsequent harvesting and processing may also be

carried out under sterile conditions.

The ratio of the extract to the carrier may be anywhere within a large range of

possible ratios. For example the ratio of base carrier to plant extract (and other additives if provided) may be anywhere between 1 to 5 and 200 to 1 (by weight). A range of 1 to 30%

by weight of extract is preferred.

Preferably the substance has a generally neutral pH in the range 6.0 to 8.0. For

example, the pH may be in the range 6.5 to 7.5.

Central nervous system disorders or the symptoms thereof which may be treated by

the active substance of the present invention include depression, anxiety, stress and epilepsy. CNS functioning may be improved or enhanced or normalised by enhancing well-being, increasing relaxation, increasing sedation, increasing coping, reducing stress, or

reducing anxiety. CNS functioning of epileptic subjects also may be improved or enhanced

or normalised by reducing incidence or by reducing severity of epileptic episodes of

changes in consciousness and/or involuntary movements. The active substance may be used as a sedative and pharmacological tests have

suggested anti-depressant and anxiolytic properties as well as cognitive enhancing and

neuroprotective effects. The active substance has a similar electroencephalo-graphic profile

to neuroleptics like chlorpromazine and may be used as an alternative to benzodiazepines thus avoiding the side effects of benzodiazepines. The active substance of the present

invention may be used as a supplement for overall well-being.

Another field of use of the active substance for improving, enhancing or normalising CNS disorders relates to behavioural disorders and developmental disorders particularly in children. For example, it is believed the active substance may be used to treat "Attention

Deficit Syndrome" (ADS), Autism, and similar disorders.

Use of the active substance as defined herein may be by external application so that

the substance is taken up by the body by absorption through the skin or mucous tissues. A

preferred method of transdermal uptake is by applying the substance to the mouth for uptake through mucous tissues of the mouth. For example, the substance may be

administered sublingually, e.g. in the form of drops of the substance taken orally and held in

the mouth under the tongue for a short time. It has been found that this method of

administration is effective for uptake of the substance into the body. A suitable formulation is available commercially under the registered trade mark ORALMAT, manufactured by

Schumacher Pharmaceuticals Pry Ltd of Melbourne, Australia. This liquid formulation has

about 1% by weight of the active refined plant extract in the carrier or excipient (including other additives). This formulation can be taken sublingually, three drops taken three times

daily, to achieve the described beneficial effect. The total daily dosage of 9 drops equals

about 0.5 ml.

It may also be possible, subject to obvious safeguards concerning the composition and

concentration of the substance and carrier to administer the substance subdermally by implant or injection.

The improvement in CNS functioning and in symptoms or functioning of epileptic

subjects was unexpected and surprising and as yet the mechanism for this activity has not

been determined.

BRIEF DESCRIPTION OF FIGURES

The invention will now be described with reference to the following non-limiting examples in which reference is made to:

Figure 1 which illustrates the electrode positions for EEG measurement in Example 1 ;

Figure 2 which shows a brain showing delta power associated with changes in

condition in Example 1 ;

Figure 3 which represents EEG power in the form of human brain maps in Example

1.

Figure 4 which shows a brain showing delta power associated with changes in

condition in Example 5; and

Figure 5 which represents EEG power in the form of human brain maps in Example

5. DETAILED DESCRIPTION

EXAMPLES RELATING TO CNS ACTIVITY

EXAMPLE 1

Background

Quantitative human electroencephalograph (EEG) methods have a well-documented

application in human psychopharmacology. In normal healthy subjects, single dose studies

have been conducted to identify drugs which affect the central nervous system (CNS),

specify the times of drug activity, compared and classify drugs, predict clinical efficacy, determine dose-response relationships with regard to CNS effects and relate EEG findings

to other measured effects (Finlc, 1969; Itil et aL, 1972; Saletu et al., 1976; 1982; 1988;

1992). The studies by Fink et al, (1969), referred to earlier, that led to the division of

psychopharmaceuticals into four classes (neuroleptics, antidepressants, tranquillisers, and

psychostimulants) was on the basis of EEG characteristics. The classification was based on two hypotheses; (1) that the different therapeutic effects of neuroleptics, antidepressants, tranquillisers, etc. are expressed in the form of different EEG effects in patients as well as

in healthy persons, and (2), that it must therefore be possible to allocate new and clinically as yet unknown substances hypothetically to a therapeutic class on the basis of their EEG

effects in healthy subjects, and then to confirm this classification in clinical trials.

These classification studies have shown that neuroleptics such as chlorpromazine and

clozapine show increases in slow frequencies (delta, theta) (1-12 Hz), and alpha activity

(8-13Hz) in healthy subjects. An increase in the beta frequencies (14-30Hz) seems to be typical for the conventional antidepressants, whereas a decrease in alpha and increase in beta activity is typical for tranquillizers and hypnotics. Psychostimulants have been shown to reduce delta and theta activity. Oralmat drops, manufactured by Schumacher Pharmaceuticals is based on an extract of the Rye plant, Secale Cereale. The extract is composed of natural phytochemicals such

as phytoestrogens Genistein, Marairesinol, Coenzyme Q10, Daidzein, Squalene, Beta 1-3

glucan, Sterols and Sterolins.

Experiment Aims

The aims of the study were to examine the electrophysiological effects of Secale

Cereale utilising EEG to examine the central nervous system (CNS) effects.

Methods

The study was conducted to examine the acute effects of placebo and two doses of

Secale Cereale (0.5ml = 9 Oralmat drops and 1 ml = 18 Oralmat drops, administered

sublingually) on spontaneous EEG using a randomised double blind, placebo controlled

design. Participants

20 healthy human participants (10 males and 10 females) (aged between 18 and 40)

were tested. Participants were selected for the study based on a detailed physical

examination by a physician. Subjects with history of cardiovascular, hepatic, gastrointestinal, endocrine, neurological conditions (including psychiatric) or glaucoma or who were currently taking any drugs were excluded from the study. A repeated measures

design was used with each participant acting as his/her own control and undergoing testing

in three treatment conditions (placebo, 0.5ml Secale Cereale and 1.0ml Secale Cereale).

Each treatment condition was separated by a 1-week washout period. This was an acute

dose response study. Timing of drug administration and EEG recordings

Recording 1 Recording 2 Recording 3

0 mins: 60 mins: 20 mins:

Placebo or 0.5 or 1.0 ml Secale Cereale

EEG recordings were taken at the following times: 0, 60 min and 120 min after drug

administration. Alpha, beta, delta and theta EEG frequencies were measured.

Recording

During each of the testing days, an electrode cap was placed on the participants head

and a water based gel was used to maintain contact between the electrodes and the scalp.

Electrophysiolo gy

Spontaneous EEG was measured in each subject to determine robust quantitative changes of large-scale neo-cortical dynamic behaviour due to administration of Secale

Cereale. The EEG data was recorded in the "resting state" meaning slowly counting

breaths to facilitate relaxation and in "cognitive states," meaning during the performance of

a demanding task.

Recording Sequence

During each of the three tests, the following was recorded with the NeuroScan™ system.

1. Three one-minute periods of eyes-closed spontaneous, resting EEG alternating with

2. Three one-minute periods of eyes-closed spontaneous, cognitive EEG.

3. Three one-minute periods of eyes-open, resting EEG alternating with

Three one-minute periods of eyes-open, cognitive EEG. EEG Recording and Processing

Salient aspects of data processing:

58 scalp sites used, (EOG & EMG to exclude artifact)

Signal filtered FFT of at least 60 sec worth EEG for each condition

^• Relative Powers calculated for principal EEG frequencies.

Frequency bands assessed:

delta - Low (1.5 - 3.5 Hz) theta - (3.5 - 7.5 Hz)

alpha (7.5 - 12.5 Hz)

beta - High (13.0 - 17 Hz)

Figure 1 illustrates the electrode positions for EEG measurement. Statistical Analyses

All data was averaged into the corresponding EEG frequency bands corresponding to

alpha, beta, delta and theta. Power was calculated at each of these frequencies and grouped

into specific electrode regions which included left frontal, left temporal, left parietal and left

occipital; right frontal, right temporal, right parietal; and all midline sites. Repeated

Measures ANOVAs were computed to assess whether statistical differences in EEG power

existed between the three treatment conditions (Placebo or 0.5 or 1.0 ml Secale Cereale). Significant differences were observed for beta and delta frequencies indicating that

particularly at frontal sites that, relative to placebo, the 1.0 ml Secale Cereale caused an increase in delta power and a decrease in beta power. These relationships are represented

figuratively in terms of brain maps in Figures 2 and 3. Two other significant findings are

worth noting here: First, the highest strength concentration of Secale Cereale produced the largest effects on both delta and beta. Second, the strongest effects were observed up to one

hour post-administration and significantly reduced at 2 hours post administration. No

changes in alpha or theta were observed.

Figure 2 shows in delta power associated with changes in condition. From top of

page (placebo) - followed by middle (0.5 ml Secale Cereale) and at bottom of page (1.0 ml Secale Cereale). Changes are most evident at frontal brain sites.

Figure 3 presents EEG power figuratively represented in human brain maps. Placebo,

0.5ml Secale Cereale, and 1.0ml Secale Cereale are presented from top to bottom.

Discussion

The brain maps and statistical analyses indicate effects of Secale Cereale on the

central nervous system. The results indicate the administration of Secale Cereale increased

delta activity and reduced beta activity, particularly at frontal electrode sites. Frontal areas

of the brain have been implicated in human executive functioning as well as in inhibitory

processes that are thought to govern various emotional and behavioural processes collectively underlying subjective states, mood, personality and the experience of emotions.

At the dosages tested the pattern of results suggest that the Secale Cereale may act similarly

to existing drugs in terms of decreasing beta power and increasing delta power. Increased

dosages to those tested, e.g. 5 ml of Oralmat drops may significantly increase the effects.

Table 1 displays the potential overlap of EEG frequencies activated by other drug

classes and types that show a similar comparison profile to Secale Cereale. Table 1 : EEG profile of some commonly used drugs

EXAMPLE 2

Anecdotal reports indicate efficacy of the active substance in the form of the Oralmat

Drops Solution for normalising Attention Deficit Syndrome (ADS) in children.

One report relates to an 11 year old asthmatic boy who could not be left alone with

his younger brother because he is physically violent towards him. Since taking Oralmat

Drops to treat his asthma (successfully) he has normalised and shows no violence now

towards his brother.

There are further analogous reports of uncontrollable ADS affected children behaving

normally after taking Oralmat Drops.

Oralmat Drops may also be an effective treatment for Autism and similar indications.

EXAMPLES RELATING TO EPILEPSY

Because the examples relating to the treatment of epilepsy disorders and symptoms

are to some extent anecdotal in nature, it is possible that the product of the present

invention and its method of use will not show efficacy or will show varying degrees of efficacy in the treatment of each and every type of epilepsy. Because epilepsy is not a specific disease but rather a complex of symptoms that can result from a number of different conditions (as outlined in the early part of this specification), some types of

epileptic subjects may not be effectively treatable, or their symptoms treatable, using the

products, uses and methods of the present invention. Hence further research may be needed

to identify types of epilepsy susceptible to treatment by the products, uses and methods of

the present invention.

EXAMPLE 3

An adult woman who had suffered epileptic fits for 17 years, substantially on a daily

basis, commenced using Oralmat Drops according to the recommended dosage and mode of

administration, namely three drops administered sublingually three times daily. The

occurrence of the epileptic fits stopped. The woman continued taking the Oralmat Drops in

this mam er for about two months without recurrence of the epileptic fits.

After about two months, the woman stopped taking the Oralmat Drops, whereupon

the recurring episodes of seizures recommenced.

After a further short time, the woman resumed taking the Oralmat Drops as

prescribed and the epileptic seizures again ceased recurring. The woman has remained on

the regime of daily Oralmat Drops administered sublingually three times daily without the

epileptic fits recommencing.

EXAMPLE 4

A human subject who had suffered from recurring epileptic fits commenced taking

Oralmat Drops, three drops administered sublingually three times daily and, after

commencement of this treatment regime, the epileptic seizures ceased. The subject has not discontinued taking the Oralmat Drops and has had no epileptic seizures or fits since

commencing this treatment regime. FURTHER EXAMPLE RELATING TO CNS ACTIVITY

EXAMPLE 5

Experiment 1

The purpose of the research was to examine the power of the alpha, beta, delta and

theta bands of the human electroencephalogram (EEG) after administration of Oralmat™

Drops solution.

The EEG profile has historically been used in psychopharmacology to identify the

action of a new drug/substance on the human brain. For instance a cognitive enhancer would be expected to change alpha activity whereas an anxiolytic drug would be expected

to change beta power. This methodology has been used extensively in the past and detailed

EEG profiles of nearly every CNS active drug is available. Establishing the EEG profile (as

will be explained in more detail later) is a necessary first step in understanding its mode of

action on the human brain and on behaviour.

Experimental aims The aims of the study were to :

1. examine the electrophysiological effects of Secale Cereale utilising EEG to examine the

central nervous system (CNS) effects;

2. examine the CNS electrophysiological effects over time, to examine duration of CNS

activity; and

3. examine dose-response CNS effects and to examine the therapeutic class of Secale

Cereale on the basis of the EEG. Method

The study was conducted to examine the acute effects of placebo and two doses of

Secale Cereale (0.5ml and 1 ml) on spontaneous EEG using a randomised double blind, placebo controlled design. All subjects were thoroughly briefed on all study procedures and

their rights and obligations as a subject prior to recruitment.

Participants

25 healthy human participants (10 males and 10 females) (aged between 18 and 40)

were tested. Participants were selected for the study based on a detailed physical

examination by a physician. Subjects with history of cardiovascular, hepatic,

gastrointestinal, endocrine, neurological conditions (including psychiatric) or glaucoma or

who were currently taking any drugs were excluded from the study. Testing was conducted

at the EEG suite, Neuropsychology Laboratory. A repeated measures design was used with each participant acting as his/her own control and undergoing testing in three treatment

conditions (placebo, 0.5ml Secale Cereale and 1.0ml Secale Cereale). Each treatment

condition was separated by a 1-week washout period. This was an acute dose response

study.

Timing of drug administration and EEG recordings

Recording 1 Recording 2 Recording 3

O mins 60 mins 120 mins

Placebo or 0.5 or 1.0 ml Secale Cereale

EEG recordings were taken at the following times: 0, 60min and 120min after drug administration. Alpha, beta, delta and theta EEG frequencies were measured. Recording

During each of the testing days, an electrode cap was placed on the participants head

and a water based gel was used to maintain contact between the electrodes and the scalp. Electrophvsiolo gy

Spontaneous EEG was measured in each subject to determine robust quantitative

changes of large-scale neo-cortical dynamic behaviour due to administration of Secale

Cereale. The EEG data was recorded in the "resting state" meaning slowly counting breaths

to facilitate relaxation and in "cognitive states," meaning during the performance of a

demanding task.

Recording Sequence

During each of the three tests, the following was recorded with the NeuroScan™ system.

1. Three one-minute periods of eyes-closed spontaneous, resting EEG alternating with

2. Three one-minute periods of eyes-closed spontaneous, cognitive EEG.

3. Three one-minute periods of eyes-open, resting EEG alternating with

4. Three one-minute periods of eyes-open, cognitive EEG.

EEG Recording & Processing

Salient aspects of data processing:

58 scalp sites used, (EOG & EMG to exclude artifact)

Signal filtered

FFT of at least 60 sec worth EEG for each condition

Relative Powers calculated for principal EEG frequencies

Frequency bands assessed:

delta - Low (1.5 - 3.5 Hz) theta - (3.5 - 7.5 Hz)

alpha - (7.5 - 12.5 Hz)

beta - High (13.0 - 17 Hz).

Figure 1 illustrates the electrode positions for EEG measurement.

Statistical analyses

All data was averaged into the corresponding EEG frequency bands corresponding to

alpha, beta, delta and theta. Power was calculated at each of these frequencies and grouped

into specific electrode regions which included left frontal, left temporal, left parietal and left

occipital; right frontal, right temporal, right parietal; and all mideline sites. Repeated Meas-

ures ANOVAs were computed to assess whether statistical differences in EEG power ex¬

isted between the three treatment conditions (Placebo or 0.5 or 1.0 ml Secale Cereale). Sig¬

nificant differences were observed for beta and delta frequencies indicating that particularly

at frontal sites that relative to placebo the 1.0 ml Secale Cereale caused an increase in theta power and a decrease in beta power. These relationships are represented figuratively in terms of brain maps in figures 4 and 5. Two other significant findings are worth noting here.

First, the highest strength concentration of Secale Cereale produced the largest effects on

both delta and beta. Second, that the strongest effects were observed up to one hour post-

administration and significantly reduced at 2 hours post administration. No changes in Al¬

pha or theta were observed.

Figure 4 shows changes in delta power associated with changes in condition. From

top of page (placebo) followed by middle (0.5 ml Secale Cereale) and at bottom of page (1.0 ml Secale Cereale). Changes are most evident at frontal brain sites.

Figure 5 present EEG power figuratively represented in human brain maps. Placebo, 0.5m Secale Cereale and 1.0 ml Secale Cereale are presented from top to bottom. Discussion

The brain maps and statistical analyses indicate preliminary effects of Secale Cereale

on the central nervous system. These effects may help explain the behavioural and/or emo¬

tional effects reported by consumers of the Secale Cereale. The results indicate the admini-

stration of Secale Cereale increased delta activity and reduced beta activity, particularly at

frontal electrode sites. Frontal areas of the brain have been implicated in human executive

functioning as well as in inhibitory processes that are thought to govern various emotional

and behavioural processes collectively underlying subjective states, mood, personality and

the experience of emotions. The pattern of results suggest that the Secale Cereale may act

similarly to existing drugs in terms of decreasing beta power and increasing delta power.

However existing drugs that change these frequencies also appear to change alpha and theta

power, again suggesting a unique profile for Secale Cereale. An alternative explanation is

that the concentration of the agent was not sufficient for us to detect changes in alpha and

theta activity.

Table 2 displays the potential overlap of EEG frequencies activated by other drug

classes and types that show a similar comparison profile to Secale Cereale.

Table 2: EEG profile of some commonly used drugs

The results of experiment 5 suggest a combination effect mirroring some of the ef¬

fects of drugs that exert sedative properties. This may also be consistent with anecdotal

claims by consumers who use the Oralmat drops of subjective feelings of well-being and re-

laxation. Further research is required to replicate and confirm this profile using higher

doses. As you can see from the caffeine profile, as one increases the dose of caffeine, some

of the frequencies progressively become activated. For example at 100 mg, theta, beta, and

alpha are not activated, but at 500 mg all four bands are activated. This is a comparison that

is obviously relevant for our purposes. A higher dose of Secale Cereale may activate the

other frequencies and this information will be very useful in allowing us to more definitively describe the actions of Oralmat Drops.

Interestingly the largest effect was at frontal sites and involved the 1.0 Secale Cereale

dose indicating that as dose increases so does the effect on these frequencies. These data

therefore suggest that higher doses of Secale Cereale, perhaps at 2.0 or 5.0 ml would be

more appropriate in evoking a larger brain response at these frequencies. It is also possible

that smaller effect on the other frequencies could also be observed at higher doses. It is in¬

terestingly that alpha and theta frequencies were not modified by the Secale Cereale which may therefore suggest a unique drug effect on the brain or that the dose of Secale Cereale

was not sufficient for us to observe a change for these frequencies.

This study was an acute study, that was conducted to examine for the first time the

pharmaco-EEG profile of Secale Cereale. However, a chronic study may also uncover im-

portant information about the long term effects of Secale Cereale on the human EEG and

should be attempted in the future.

Another interesting finding was that the strongest effects occurred before 1 hour after

administration with most effects reducing significantly at 2 hours. This result indicates a

specific kinetic profile for Secale Cereale that should be further evaluated by future re-

search. This information may assist in the development of appropriate user product infor¬

mation and scientifically further elucidation of potential mechanisms underpinning this in¬

teresting pharmacological agent.

Conclusions

Administration of 1.0 mg of Oralmat drops solution significantly increases frontal

delta and reduced frontal beta activity. This EEG profile is unlike other commonly used

drug profiles. However there are some similarities particularly in the area of

sedation/relaxation but there are other possibilities. Future research should be conducted to

replicate and extend these results. Firstly a study in which we significantly increase the concentration of the active substance in Oralmat Drops and measure the EEG profile may fur-

ther elucidate the effect of Oralmat drops on the brain and allow us to more specifically al¬

locate it to a therapeutic class of drugs. Second and possibly in parallel a study in which the

claims of subjective well-being and general improvement sin health are objectively tested

could also be undertaken. There is no doubt that the Oralmat drops solution is active in the

CNS, however more research is required for us to be confident in ascribing its actions accurately. This notwithstanding there is some preliminary evidence that Oralmat drops

may be useful in increasing sedation and relaxation.

Scientific Priorities for research on Oralmat (in order of importance)

EEG study using 5.0ml concentration (acute)

Immune/subjective well being study (chronic study for 60 days) in which we measure immune system properties and objective assessment of general health, stress, anxiety and cop¬

ing before and after administration of Oralmat for 60 days.

EEG study assessing chronic changes in EEG (again over either 30 or 60 days

If sedative/anti-depressant/anxiolytic properties could be confirmed by this research

then other clinical trials could then be undertaken.

Experiments Two and Three

The purpose of experiment two was to more specifically test the anxiolytic/sedative

properties of the rye extract. In order to do this we conducted a randomised double blind

placebo control study in which we administered the 1.0 ml rye extract daily or placebo daily

for 8 weeks to 80 healthy participants. Baseline and 8 week measurements were assessed

for stress, anxiety and mood as well as a limited set of immune system properties.

If the rye extract possessed sedative/anxiolytic properties then it was expected that the

active group (rye) would show a decrease in measures of anxiety, stress and mood across

the two months. Statistical analyses however did not reveal any significant changes across

the two-month administration relative to the placebo condition. This indicates that either the

behavioural manifestation of anxiety and stress are not improved by administration of the rye extract or that the changes in anxiety and stress are only acutely observed. That is,

changes in anxiety and not seen over a period of time but rather within a very short period

of time (less than an hour). Future experiments are needed to further examine this possibility. It is also possible that a group of very highly stressed individuals may have bet¬

ter revealed an anxiolytic effect of the extract. However, the statistical analyses, although

not significant all supported a stimulant type effect rather than an anxiolytic effect, a gen¬

eral finding that was generally supported by the third study and is not entirely inconsistent

with the results of the first experiment. However the results of the first experiment better

explained an anxiolytic effect there was some evidence for a stimulant effect.

Experiment 3 attempted to replicate the results of Experiment 1 and again used elec¬

trophysiological methods to assess the acute effects of 1.0ml, 5.0ml and placebo conditions

on the human brain activity. Apart from the change of dose (.5 ml was replaced with 5.0ml

condition) all procedures and methods were identical to Experiment 1. Again 20 partici¬

pants completed 3 conditions.

The results of this experiment were stronger than any of the other studies. Interest¬

ingly the higher dose was not the most active dose, with the 1.0ml dose being the most ac¬

tive condition. The effect is one of a stimulant drug profile, although somewhat unique in nature. Large differences in beta and small increases in alpha activity and decreases in slow

wave activity (delta and theta activity).

General Discussion and Conclusions

The addition of the results of Experiments Two and Three of Example 5 have helped

clarify some of the basic mechanisms of the rye extract. Although the results are not as

large and or consistent as we might prefer, there are some consistencies now across the

three studies and we are slowly piecing the jigsaw together to understand this complex natu¬

ral product. The results of Experiment Three indicate a cognitive enhancing or perhaps a stimulant property of the extract which may explain why no anxiolytic effects were observed in the second study. Contrasting these results, there have been many anecdotal claims that the extract brings a feeling of relief and calmness after administration. These are

essentially subjective claims are not necessarily invalidated but also be understood by a stimulant mode of action which may improve a person's attentional and cognitive processes

(ie stimulate cognitive processes). This is not entirely inconsistent with the results of Ex-

periment One in which the main effects were not very strong relative to Experiment Three.

It is to be understood that various alterations, modifications and/or additions may be

made to the features of the possible and preferred embodiment(s) of the invention as herein

described without departing from the spirit and scope of the invention.

When used in this specification and claims, the terms "comprises" and "comprising"

and variations thereof mean that the specified features, steps or integers are included. The

terms are not to be interpreted to exclude the presence of other features, steps or

components.

Claims

CLAIMS:

1. A pharmacologically or therapeutically effective composition for the treatment of a

central nervous system disorder, said composition including a pharmacologically or

therapeutically effective amount of an extract from one or more cereal plants, said extract

including a pharmaceutically acceptable extract derived from juice of said cereal plant or

plants, together with a pharmaceutically acceptable carrier or excipient therefor.

2. A composition according to claim 1, wherein said central nervous system disorder

includes one or more of the following symptoms: depression, nervousness, tension, panic

disorder, agoraphobia, anxiety, insomnia caused by anxiety and stress.

3. A composition according to claim 1 or 2, wherein said extract has neuroleptic

activity.

4. A composition according to claim 1 or 3, wherein said central nervous system disorder

includes Attention Deficit Syndrome (ADS), autism and related disorders.

5. A composition according to claim 1, wherein said central nervous system disorder is

epilepsy or a type of epilepsy.

6. A composition according to any one of the previous claims, wherein said cereal plant

is a wild grass.

7. A composition according to any one of claims 1 to 5, wherein said cereal plant is

selected from the group consisting of one or more of corn, rice, oats, maize, sorghum,

barley, wheat and millet.

8. A composition according to claim 1, wherein said cereal plant is Secale Cereale or

rye grass.

9. A composition according to any one of the preceding claims, wherein said juice is

derived from the green leafy or stalk part of said cereal plant at the unjointed stage of plant

development.

10. A composition according to any one of the preceding claims, wherein said juice is

5 extracted by squeezing, crushing and/or grinding and not cutting said cereal plant or part

thereof.

11. A composition according to any one of the preceding claims, wherein said carrier or

excipient includes a suitable carrier component for transdermal take up, including mucosa

tissue take up, of the active ingredients in the extract.

10 12. A composition according to claim 11 , wherein said suitable carrier component is

benzyl alcohol.

13. A composition according to any one of the preceding claims, wherein said extract

includes an anti-microbial agent.

14. A composition according to claim 13, wherein said anti-microbial agent is selected

15 from the group consisting of anti-bacterial agents, anti-fungal agents and anti-yeast agents.

15. A composition according to any one of the preceding claims, wherein said extract has

a generally neutral pH in the range 6 to 8.

16. A method for treating a patient, including an animal or human patient, having a

central nervous system disorder including administering to said patient a pharmacologically

0 or therapeutically effective amount of an extract derived from a cereal plant, said extract

including a pharmaceutically acceptable plant extract derived from juice of said cereal

plant, said extract carried in a pharmaceutically acceptable carrier or excipient.

17. A method according to claim 16, wherein said central nervous system disorder

includes one or more of the following symptoms: depression, nervousness, tension, panic

disorder, agoraphobia, anxiety, insomnia caused by anxiety and stress.

18. A method according to claim 16 or 17, wherein said extract has neuroleptic activity.

19. A method according to claim 16 or 18, wherein said central nervous system disorder

includes Attention Deficit Syndrome (ADS), autism and related disorders.

20. A method according to claim 16 , wherein said central nervous system disorder is

epilepsy or a type of epilepsy.

21. A method according to any one of claims 16 to 20, wherein the extraction process is

effective to obtain substantially only water soluble components of said juice.

22. A method according to any one of claims 16 to 21 , wherein said extract is

concentrated by partial or total dehydration prior to mixing with the carrier or excipient.

23. A method according to any one of claims 16 to 22, wherein said plant extract is dried

by spray drying to produce a powder for mixing with said carrier or excipient.

24. A method according to claim 23, wherein the spray drying is carried out at a

temperature below 60°C.

25. A method according to any one of claims 16 to 24, wherein said extract is

substantially sterile when mixed with said carrier or excipient.

26. A method according to any of claims 16 to 25, wherein said extract is administered

sublingually by the application of droplets of said extract under the tongue of said patient.

27. Use of an extract from a cereal plant, said extract including a pharmaceutically

acceptable extract derived from juice of said cereal plant, in the preparation of a

medicament for the treatment of a central nervous system disorder.

28. Use according to claim 27, wherein said central nervous system disorder includes one

or more of the following symptoms: depression, nervousness, tension, panic disorder, agoraphobia, anxiety, insomnia caused by anxiety and stress.

29. Use according to claim 27 or 28, wherein said extract has neuroleptic activity.

30. Use according to claim 27 or 29 wherein said central nervous system disorder

includes Attention Deficit Syndrome (ADS), autism and related disorders.

31. Use according to claim 27, wherein said central nervous system disorder is epilepsy

or a type of epilepsy.

32. A product comprising an extract derived from a cereal plant, said extract including a

pharmocologically acceptable plant extract derived from juice of said cereal plant and

including substantially water soluble components only of said juice, wherein said extract is

effective for treating an animal or human patient having a central nervous system disorder.

33. A product according to claim 32 wherein said patient is a human.

34. A method according to any one of claims 16 to 26 wherein said patient is a human.

35. A pharmacologically or therapeutically effective composition for the normalisation

of the central nervous system function of a human or animal subject, said composition

including a pharmacologically or therapeutically effective amount of an extract from one or

more cereal plants, said extract including a pharmaceutically acceptable extract derived

from juice of said cereal plant or plants, together with a pharmaceutically acceptable carrier

or excipient therefor.

36. A composition according to claim 35 wherein the normalisation of the central nervous

system function involves cognitive enhancement or cognitive stimulation.

37. A method for treating a animal or human patient having a condition requiring

normalisation of central nervous system function including administering to said patient a pharmacologically or therapeutically effective amount of an extract derived from a cereal

plant, said extract including a pharmaceutically acceptable plant extract derived from juice

of said cereal plant, said extract carried in a pharmaceutically acceptable carrier or excipient.

38. A method according to claim 37 wherein the normalisation of the central nervous

system function involves cognitive enhancement or cognitive stimulation.

39. Use of an extract from a cereal plant, said extract including a pharmaceutically

acceptable extract derived from juice of said cereal plant, in the preparation of a

composition for the normalisation of central nervous system function.

40. Use according to claim 39 wherein the normalisation of the central nervous system

function involves cognitive enhancement or cognitive stimulation.

41. A product comprising an extract derived from a cereal plant, said extract including a pharmocologically acceptable plant extract derived from juice of said cereal plant and

including substantially water soluble components only of said juice, wherein said extract is

effective for the normalisation of central nervous system function in an animal or human

patient.

42. A product according to claim 39 wherein the normalisation of the central nervous

system function involves cognitive enhancement or cognitive stimulation.