BACKGROUND OF THE INVENTION

This invention relates to therapeutic compositions containing betaine salts.

Betaine, a quaternary nitrogen compound, is a metabolic byproduct of choline oxidation. Barak et al. (1983) Life Sciences 32, 771-774 suggests that betaine may serve as a methylating agent when normal methylating pathways are impaired by ethanol ingestion, drugs, or nutritional imbalances. Moyrand et al. (1978) M.C.D. 7, 453-457, describes the use of effervescing betaine citrate to treat patients suffering from dyspepsia and exhibiting symptoms including slow digestion, somnolence, and anorexia; betaine citrate, mixed with several additional ingredients, was administered in three 2 g doses daily for a minimum of 15 days and was found to be effective in the treatment of dyspeptic syndrome. French Patent No. 2590 M of 1963 describes the combination of less than one gram of betaine citrate with aspirin to buffer the aspirin.

SUMMARY OF THE INVENTION

In general, the invention features, in one aspect, a medicinal composition including a hangover symptom relieving amount of a pharmaceutically acceptable, non-toxic salt of betaine (preferably betaine citrate) alone or together with one or more of a pain relieving amount of an analgesic such as aspirin, a para-aminophenol derivative (preferably acetaminophen) or ibuprofen, an acid buffering amount of a buffering agent, and, optionally, an alertness inducing amount of caffeine.

In another aspect, the invention features a method of treating a human in need of relief of hangover symptoms comprising administering to the human a symptom relieving amount of a pharmaceutically acceptable, non-toxic salt of betaine.

In another aspect, the invention features a method of treating a human in need of the relief of symptoms related to ingestion of an alcoholic beverage including treatment of acute alcoholic intoxication and ethylic comas comprising administering to the human a symptom relieving amount of a pharmaceutically acceptable, non-toxic salt of betaine.

Preferably in the above methods the betaine salt, alone or together with the analgesic, caffeine, or buffering agent, is provided in admixture with a non-toxic, pharmaceutically acceptable carrier substance in the form of, e.g., a tablet, capsule, or liquid for oral administration.

The invention provides treatment for:

hangover symptoms,

undesirable symptoms associated with the presence of ethanol in the blood and

lowering of blood ethanol level.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

The activity of the composition according to the invention may be appreciated from the following experimentations:

I - HANGOVER

(a) DOSE/ACTIVITY PSYCHOMETRICS

Betaine Citrate or Placebo was administered to 6 healthy male volunteers both immediately (21H00) after and 11 hours (8H00, the day after), post ingestion of a standardized dose of alcohol (1.2 g ethanol/kg bodyweight in whisky taken between 20H00 and 20h30. Two dosing levels of Betaine Citrate (6 g and 12 g) were employed in a three-way crossover study which was carried out under double blind conditions. The treatment levels were allocated according to a randomized balanced latin square design. Psychometric testing was carried out pre-alcohol, one hour after the termination of the alcohol dose and 1 hour and 2.5 hours after the second dose of Betaine Citrate. This was administered on the morning of day 2 of each dosing stage. The dosing schedule is summarized as follows:

______________________________________DOSAGE SCHEDULESHours20.00-20.30       21.00      08.00______________________________________A      Alcohol        Placebo    PlaceboB      Alcohol        Betaine    Betaine                 Citrate    Citrate                 (6 g)      (6 g)C      Alcohol        Betaine    Betaine                 Citrate    Citrate                 (12 g)     (12 g)______________________________________

Subjects were assigned to the dosage schedules according to the following randomised balanced latin square.

______________________________________Subject No.     Period 1     Period 2 Period 3______________________________________1         A            B        C2         B            C        A3         C            A        B4         A            C        B5         C            B        A6         B            A        C______________________________________

Analysis

Statistical analysis of the psychometric data consisted of a two-way Analysis of Variance (Treatments x Times) with repeated measures on the times factor. This analysis was supplemented by a series of t-tests which utilized difference scores. Thus, differences from pre-dose values at each testing time post dose for the active dosing groups were compared with the corresponding difference scores for the alcohol+placebo group. In this way any changes from pre-dose values for the alcohol and Betaine Citrate groups would be identified if they differed to a statistically significant extent from the corresponding change from pre-dose scores for the alcohol and placebo group.

Results

The two-way Analysis of Variance of the performance and mood variables identified significant main effects for the Critical Flicker Fusion measure on the "Dose" factor. Significant differences were also found to exist on the "Times" factor for Simple Reaction Time and for the Finger Dexterity Test, Level 1. The absence of "Interaction" effects however suggests that there is no overall difference between the dose response profiles for the active and placebo groups. Thus, the direction of the changes in the performance and mood scale scores is for the most part consistent across each of the three treatments.

The t-test analysis of the difference scores indicates however that the extent of the impairment after the alcohol dose does differ across the respective dosing stages. Subjects scored significantly lower on the Hand Tremor test, 1 hour after receiving alcohol and Betaine Citrate (6 g and 12 g) than they scored 1 hour after receiving alcohol and placebo.

Similarly, subjects rated themselves more "contented" and more "tranquil" 1 hour after alcohol and Betaine Citrate (12 g) than they did 1 hour after receiving alcohol and placebo. Subjects also rated themselves more "happy" 2.5 hours after ingestion of the second dose of Betaine Citrate (12 g) than they did at the corresponding test session after receiving placebo.

Further inspection of the data indicates that subjects were less impaired 1 hour following alcohol and Betaine Citrate than they were after receiving alcohol and placebo for another five of the performance test measures (Simple Reaction Time, Critical Flicker Fusion, Finger Dexterity Test (Level One), Digit Copying and Mental Arithmetic). The effect also appeared to be dose-related, being more evident following the 12 g dose of Betaine Citrate than following 6 g.

(b) EFFECTS OF BETAINE AND ANALGESIC THE MORNING AFTER ALCOHOL ADMINISTRATION

One way of comparing the effects of betaine and analgesic the morning after alcohol administration is to look at the changes in subjective assessment of mental state together with actual measures of performance efficiency before and after the administration of the two substances.

For an overall comparison of the four treatments--analgesic & betaine citrate 6 g (D), placebo analgesic & betaine citrate 6 g (E), analgesic & placebo-betaine (F), placebo-analgesic & placebo-betaine (G)--a simple ranking of the changes over the morning will give us an indication of the relative efficacies of these treatments, taking into consideration: attentional efficiency, memory, and subjective assessments of mental state.

Of the measures of attentional efficiency, the speed of reaction in the raid information processing test was the most statistically significant (F=23.8, dg=3,165, p<0.00001). The two measures of memory were both highly significant (F=34.9, df=3,165, p<0.000001; and F=69.5, df=3,209, p<0.0000001, respectively). Of the subjective assessments, alertness was the most reliable (F=13.1, df=3,165, p<0.0001). The changes in each of the four conditions following the treatments are presented below for each of these measures, together with the rankings.

This experimentation was undertaken three times with the same conditions of alcohol intake and hours of treatment as above; in the first experimentation, analgesic was acetyl salicylic acid (1 g), in the second, paracetamol (0.66 g) and in the third ibuprofen (0.8 g). As the results of these three experimentations lead to the same final ranking, only the first one is described in details.

______________________________________    RANKINGS    D    E      F      G    D    E   F    G______________________________________Reaction Time-      19     24     18   13   2    1   3    4msec (increase inspeed followingtreatment)Memory - numberof words recalled(change + or -followingtreatment)Immediate recall      0.8    0.4    0.8  -1.3 1.5  3   1.5  4Delayed recall      -0.4   -1.1   -0.4 -2.6 1.5  3   1.5  4Self rated alert-      11.2   13.4   8.6  4.6  2    1   3    4ness mm (Increasein alertness fol-lowing treatment)    MEAN RANKINGS 1.75   2.0   2.25 4.0______________________________________

Friedman's Two Way ANOVA by ranks was applied to the data and yielded a value of Chi=7.5, df=3, which only just missed significance at the 5% level (7.82) but was much higher than the value for the 10% level (6.25), and thus shows an interesting trend.

This analysis has therefore shown that the relative efficiency of the three series of four treatments is in the following order:

1. Betaine and analgesic

2. Betaine alone

3. Analgesic alone

4. Neither Betaine nor analgesic

II - BIOCHEMISTRY

(a) DOSE/ACTIVITY

For the various biochemistry parameters investigated in this study, the following plasma variables were selected for statistical analysis: Ethanol, Lactate, Acetaldehyde, Ketone Bodies, High Density Lipoproteins, Low Density Lipoproteins.

For each variable the data were subjected to a two-way analysis of variance (treatment×time) with repeated measures on the subjects. The results were then further investigated by a series of t tests utilizing difference scores. In this analysis changes from pre-dose values at each post dose testing time for the group which received alcohol+placebo, were compared with the corresponding changes for the groups receiving alcohol+betaine citrate (6 g and 12 g).

Results

The two-way analysis of variance identified significant "treatment" effects only for plasma ethanol and ketone bodies. The results reflect significant overall differences between the three treatments for these variables. Statistically significant "time" effects were also evident for ethanol, ketone bodies and acetaldehyde. However no significant "treatment×time" interactions were observed indicating that the dose response profiles were in a similar direction.

The t-test analysis of the difference scores identified a significant (p 0.05) reduction in plasma ethanol for subjects who received alcohol+12 g betaine citrate as compared to subjects receiving alcohol+placebo, one hour after completion of the alcohol intake. The mean peak plasma ethanol values for the three treatments were:

Alcohol+Placebo: 107.3 mg %

Alcohol+6 g Betaine Citrate: 91.3 mg %

Alcohol+12 g Betaine Citrate: 69.8 mg %

so that the observed trend is clearly dose related.

The corresponding t-test analysis for the other investigated variables (ketone bodies and acetaldehyde) did not reveal similar treatment associated changes.

(b) BLOOD ALCOHOL VALUES

Another experimentation has been conducted for the determination of the blood alcohol values in relationship with the treatments.

For this experimentation, 2 groups of each 6 subjects have been treated orally, a quarter of an hour after a common alcohol intake of 1.2 g/kg of whisky as follows:

the first group receives a single dose 6 g of betaine citrate and

the second group receives a single dose 6 g of placebo.

Samples of blood were collected at various times after the end of the alcohol intake and the subsequent treatment. The results appear on the following table:

______________________________________CONDITION          H     J          Blood Alcohol (mg %)______________________________________15       min         98.6    99.830       min         128.8   146.445       min         129.4   142.51        hour        129.6   142.31.5      hour        111.2   122.82        hours       102.7   116.53        hours       84.1    102.84        hours       69.3    81.8______________________________________

It appears clearly from these figures that betaine citrate administration lowers the alcohol content of blood.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

We turn now to a description of preferred embodiments of the invention.

Composition

A betaine salt, according to the invention, is ordinarily provided admixed with a non-toxic, pharmaceutically acceptable carrier substance as such, or in combination with an effective amount of one or more of analgesic such as acetyl salicylic acid, a para-aminophenol derivative, ibuprofen, a buffering agent and, optionally, caffeine. These additional ingredients, all of which are found in conventional pain or discomfort-relieving preparations, are administered in combination with the betaine salt, in conventional dosages for those substances.

These substances all exhibit short-term, acute effects, and they are thus appropriately administered in combination with a betaine salt which, according to the invention, also exhibits acute, as opposed to chronic, symptom-relieving effects.

Although the preferred betaine salt is betaine citrate, other salts, e.g. betaine/HCl and betaine aspartate, can also be used. Betaine citrate is preferable because, in addition to the therapeutic benefits conferred by betaine, the citrate provides desirable buffering of acid, in some instances obviating the use of additional acid buffering agent. In other instances, particularly where a para-aminophenol analgesic is being administered concurrently with betaine citrate, additional buffering agent, e.g. sodium citrate, is desired.

The dosage of betaine salt to be administered in an individual case will vary with factors such as the amount of ethanol contained in the ingested beverage and the metabolism of the individual. In general, the preferred daily adult dose contains about 1-24 g betaine salt, preferably 4-16 g, most preferably about 12 g. Provided in combination with the betaine salt are, optionally, one or more of: 100 mg to 400 mg of acetyl salicylic acid, 100 mg to 325 mg of a para-aminophenol derived analgesic, preferably acetaminophen; 50 mg to 200 mg of caffeine; and 1 g to 4 g of a buffering agent, preferably sodium citrate. The betaine citrate can also be provided in combination wioth an effervescing agent. When combining betaine citrate with a para-aminophenol derived analgesic, for the sake of stability, the pH of the mixture, about 2.3, should be raised to about 5.2 using a sufficient amount of the buffering agent.

Although acetaminophen (paracetamol) is the preferred para-aminophenol derived analgesic, others, e.g. phenacetin, acetanilide or acetaminosalol may be used.

In addition to buffering agents, caffeine, acetyl salicylic acid and para-aminophenol derived analgesic, the compositions of the invention can optionally contain other ingredients as well, to provide desired properties such as texture, color, flavor, and effervescence. Examples of such additional ingredients are sorbitol, methyl or propyl parahydroxybenzoate, essence of lemon, glucose, lactose, sucrose, mannitol, sorbic acid, saccharin, artificial aromas, polyethylene glycol, bicarbonate of soda, sodium saccharinate, sodium alginate, benzoic acid, erythrosin, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, sodium hydroxide and silicic acid.

Example of betaine salt-containing compositions of the invention are given below.

______________________________________Ingredients                Amount______________________________________Composition 1: effervescent tabletBetaine Citrate            3.000   gSodium Citrate             0.690   gAnhydrous Citric Acid      0.057   gSucrose                    0.348   gSodium Saccharinate        0.012   gPolyethyleneglycol         0.084   gAroma of Lemon             0.003   gAroma of Orange            0.006   gComposition 2: gel (bags)Betaine Citrate            2.000   gSaccharin                  0.010   gSodium Alginate            0.400   gBenzoic Acid               0.010   gArtificial Aroma           0.020   gErythrosin                 0.0005  gComposition 3: capsule/tabletBetaine Citrate            0.400   gIbuprofen                  0.100   gSilicic Acid               0.005   gMagnesium Stearate         0.010   gComposition 4: soluble powder (bags)Betaine Citrate            2.000   gAcetyl salicylic acid      0.200   gCaffeine Citrate           0.250   gSodium Saccharinate        0.015   gSorbitol                   2.600   gComposition 5: effervescent powder (bags)Betaine Citrate            6.000   gAcetaminophen              0.100   gCaffeine                   0.050   gCitric Acid                0.100   gSodium Bicarbonate         0.500   gSodium Saccharinate        0.010   gSucrose                    2.315   gComposition 6: tabletBetaine Citrate            0.250   gPhenacetin                 0.050   gSaccharin                  1.150   gMannitol                   0.750   gLactose                    0.200   gMagnesium Stearate         0.050   gComposition 7: capsulesAnhydrous Betaine Citrate  0.200   gPhenacetin                 0.050   gLactose                    0.060   gPure cellulose             0.040   gReticulated polyvinylpyrrolidone                      0.010   gMagnesium Stearate         0.010   gComposition 8: drop solution(100 ml bottle: daily dose)Anhydrous Betaine Citrate  16.000  gAcetaminophen              0.325   gCaffeine                   0.100   g95% Ethanol                1.000   mlSodium saccharinate        0 020   gArtificial Aroma           0.040   gSodium Hydroxide, sufficient amountfor pH 5.2Purified water, sufficient amount for100 ml.Composition 9: syrup (bottle of 15 ml: daily dose)Anhydrous Betaine Citrate  5.0000  gAcetaminophen              0.2100  gCaffeine                   0.1200  gSucrose                    6.0000  gSodium Saccharinate        0.0120  g95% Ethanol                1.5000  mlMethyl Parahydroxybenzoate 0.0096  gPropyl Parahydroxybenzoate 0.0024  gArtificial Aroma           0.0300  gArtificial Orange Color    0.0003  gAqueous sodium Hydroxide (30 g/100 ml),sufficient amount for pH 5.2.Composition 10: drop solution (4 ml phial)Anhydrous Betaine Citrate  1.200   gPhenacetin                 0.160   gCaffeine                   0.110   g95% Ethanol                1.000   mlSodium Saccharinate        0.025   gArtificial Aroma           0.050   gSodium Hydroxide, sufficient amount for pH 5.2Composition 11: effervescent powder (bag)Betaine Citrate            2.000   gAcetanilide                0.150   gCaffeine                   0.060   gCitric acid                0.120   gSodium Bicarbonate         0.400   gSodium Saccharinate        0.020   gLactose                    5.040   gComposition 12: effervescent powder (bags)Betaine Citrate            2.000   gAcetyl salicylic acid      0.200   gCaffeine Citrate           0.150   gSodium Bicarbonate         0.500   gSodium Saccharinate        0.015   gLactose                    3 000   gArtificial Aroma           0 050   gComposition 13: so1uble powder (bag)Betaine Citrate            1.000   gAcetaminosalol             0.320   gCaffeine Citrate           0.150   gSodium Saccharinate        0.020   gSorbitol                   2.500   gComposition 14: gel (bags)Betaine Citrate            2.000   gAcetaminosalol             0.250   gSaccharin                  0.040   gSodium Alginate            0.200   gArtificial Aroma           0.030   gComposition 15: gel (bags)Betaine Citrate            2.000   gAcetyl salicylic Acid      0.110   gSaccharin                  0.010   gSodium Alginate            0.400   gArtificial Aroma           0.025   gComposition 16: soluble powder (bag)Betaine Citrate            2.000   gIbuprofen                  0.150   gCaffeine Citrate           0.150   gSodium Saccharinate        0.050   gSorbitol                   2.000   gComposition 17: effervescent tabletBetaine Citrate            3.000   gCaffeine Citrate           0.150   gSodium Citrate             0.500   gAnhydrous Citric Acid      0.057   gGlucose                    0.400   gSodium Saccharinate        0.020   gPolyethyleneglycol         0.060   gComposition 18: effervescent tabletBetaine Citrate            3.000   gAcetaminophen              0.150   gCaffeine                   0.100   gSodium Citrate             0.690   gAnhydrous Citric Acid      0.057   gGlucose                    0.400   gPolyethyleneglycol         0.084   gAroma of Orange            0.006   gSodium Hydroxide, sufficient amountfor pH 5.6Composition 19: effervescent tabletBetaine Citrate            1.750   gAcetyl salicylic acid      0.250   gSodium Bicarbonate         1.500   gSaccharin Sodium           0.003   gLubricant (Stearic Acid/Magnesium                      0.002   gstearate Mixture - 10/1 ratio)                      0.002   g                      3.505   g______________________________________

Use

Betaine salt is orally administered, according to the invention.

To treat symptoms related with the ingestion of alcoholic beverages (hangover Syndrome), betaine salt is administered in single doses of 1-24 g, preferably 4-16 g, most preferably about 12 g, between one and five times per day.

Hangover symptoms are associated with recent overindulgence with alcoholic beverages. In general, hangover symptoms occur when at least about three hours, and not more than about two days, have elapsed since the ingestion of said alcoholic beverages. It is during this time period, when the hangover symptoms are present, but the ethanol has been largely metabolized, that the administration of betaine salt to treat hangover symptoms is carried out.