CA1149740A - Pharmaceutical and dietary composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compositions and use of .gamma.-linolenic acid and related materials with ascorbic acid, or ethyl alcohol, or an opiate antagonist such as naloxane, nalorphine or levallorphan, for treating alcoholism or moderating the effects of taking alcohol.

Description

7~0 YIELD OF T~E INVENTION
.
This invention relates to co~positions for the treatment of certain diseases and disorders primarily, but not exclusively, in the field of human medicine.
GENERAL BACKGROUND
Considerable interest has been shown in recent years in the use of prostaglandin (PG) precursors in medicine.
For various reasons it is not practical to administer naturally-occurring prostaglandins such as PGE 1 and PGE 2 to patients. Consequently, considerable attention has focussed on the use of prostaglandin precursors including linoleic acid, y-linolenic acid (GLA) and dihomo-y-linolenic acid (DGLA).
Conversion of these materials in the body is believed to be as shown in the following diagram:

~,.

cis- Linoleic Acid (9, l2 - octadecadienoic acid ) GLA
(6, 9,12 - octadecatrien~ic acid ) ~GlA DGLA I series ester ~ (5,8,11 - eicosatri~noic acid) - endoper~xides ~eserves (small~
1 series ~G.'S

LArgster AA
~eserves _ - (Arachldoni c acid, ie.
$,8,1',14-eicosat~traenDic ~;id)

2 series endoperoxides ~ ~l~
TXA2 PGF2 a PGI2 PGE2 etc., (Thromboxane A2) 2 Series PG s .. . . ... . . . .. . . ..

74~

The ~road outline of this pathway is well known, and it brings out clearly that a major function of essential fatty acids (EFAs) is to act as precursors for prostaglandins, 1 series PGs being formed from dihomo-y-linolenic acid (DGLA) and 2 series PGs from arachidonic acid (AA). DGLA and AA are present in food in only small quantities, and the major EFA in food is linoleic acid which is first converted to y-linolenic acid (GLA) and then to DGLA and AA. The conversion of linoleic acid to GLA is blocked by a high fat and high carbohydrate diet, by ageing and for example by diabetes. Stores of AA in the body in the form of lipid esters are very large indeed. In contrast only small amounts of DGLA
ester are present.
INVENTION AND BACKGROUND
DGLA is the key substance. GLA is almost completely and very rapidly converted in the body to DGLA and so for practical purposes the oral administration of DGLA and GLA amounts to the same thing.
DGLA can he converted to a storage form, changed to arachidonic acid and thence to PGs of the 2 series, or converted to PGs of the 1 series.
There is increasing evidence that PGs of the 1 series play a vital role in a number of key areas. First, PGE 1 activates T lymphocytes. Defective T lymphocytes are believed to be involved in causing a wide range of allergic and inflammatory disorders and in making individuals susceptible to cancer and infections of all types. Second, PGE 1 is important in preventing over-production .

97~0 of collagen and fibrous tissue, a factor which plays a major role in arthritis and the so-called collagen diseases. Third, PGE 1 levels are extremely low in patients with schizophrenia and are moderately low in patients with depression. Eourth, PGE 1 appears to be important in controlling cholesterol levels and necessary for the normal actions of insulin. Fifth, PGE 1 dilates blood vessels and may be expected to be helpful in any situation in which vessel spasm occurs. Sixth, PGE 1 appears to inhibit the production of 2-series PG's, levels of which are raised in a wide variety of inflammatory disorders. Seventh, PGE 1 increases production of cyclic AMP which has anti-inflammatory effects.
There are therefore very strong reasons, and this broadly is an aim of the present invention, for influencing the l-series/2-series PG balance in the body in favour of l-series PG ' s and specifically for selectively enhancing formation of PGs of the l-series and particularly P OE 1. The diseases and disorders below are among thcse in which such action is indicated:
1. Situations in which defective T lymphocyte function has been described such as allergic and inflammatory disorders, multiple sclerosis, schizophrenia and cancer.
2. Situations in which regulation of collagen formation and breakdown is defective including rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease and the various "collagen"
diseases.
25 3. Nental illnesses in which low PGE l levels have been reported, ~g7~0 including depression and schi7ophrenia. In depression, platelet PGE 1 production is moderately reduced whereas in schizophrenia it is severely reduced.
g. Disorders of lipid and carbohydrate metabolism in particular diabetes mellitus and situations in which blood cholesterol levels are elevated.
5. Disorders in which there is a tendency of blood vessels to go into spasm such as angina pectoris, myocardial infarction and Reynaud's syndrome.
10 6. Disorders of inflammation in which there may be excessive production of 2-series PGs from arachidonic acid, often coupled with low levels of cyclic ~MP.
Selective enhancement of l-series PG production has been explored in human platelets. The method is given in detail later herein but briefly human platelets are incubated with radioactive DGLA or arachidonic acid. The PGs produced during incubation are extracted by conventional means and separated by thin layer chromatography, and the amount of radioactivity appearing in each PG or related substance is counted. PGE 1, PGF 1~ and thromboxane Bl from DGLA, and PGE 2, PGF 2~ and thromboxane B2 from AA are estimated. The results, as given herein, demonstrate the inventor's belief that the effects of various agents on AA and DGLA conversion can be quite different and that it is possible to selectively enhance formation of PGE 1 and other l-series PG compounds.
The effect is believed to be by influencing the conversion of DGLA

7~0 to the l-series PGs.
The balance between l-series and 2-series PGs is, the inventor believes, significant in terms of overall control of the convers-on pathways given earlier. Such control is not understood in detail but without restriction to the theory it appears first that PGE 2 is able to enhance the formation of l-series PG's~
and second that PGE 1 is able to block arachidonic acid mobilisation from tissue stores. Thus the conditions for a negative feedback control loop exist; overproduction of PGE 2 from AA will activate PC~ 1 synthesis, the PGE 1 will inhibit AA mobilisation, and production of 2-series PG's will drop. Further, TXA 2, an unstable product of the 2-series endoperoxides arising in 2-series PG
production, also appears to enhance l-series PG and in particular POE 1 production. Thus again the activity of the 2-series PG
15` synthesis pathway gives rise indirectly to a material that controls that pathway.
The inventor has found that the opiate antagonist naloxone, at 20 ~g/ml, reverses an effect of l-levorphanol at 100 ~g/ml in inhibiting conversion of DGLA to PGE 1. The d-isomer of levorphanol, which is devoid of opiate activity, had no such effect. The reversal indicates that activation of opiate receptors inhibits PGE 1 formation and thus that endogenous opioids, and opioids formed in the gut from partial protein digestion, may inhibit PGE 1 formation.
This inhibition is reversed by opiate antagonists such as naloxone, desirable in situations where opiate excess is suspected such as ~9~LO

schizophrenia, coeliac disease and psoriasis. It should be note that an opiate action is by definition one activated by 1- but not by d-levorphanol and that an opiate antagonist is a material blocking this l-levorphanol activation.
Morphine and related opiate drugs have actions on many tissues of the body. These actions are believed to be due to activation of a specific "receptor" which is chemically complementary to the drugs.
The opiate receptor is identified in three main ways:
1. Morphine and drugs with a similar action activate it and produce a biological effect.
2. l-levorphanol binds to and activates the opiate receptor whereas its d-isomer does not. Effects which are produced by l-levorphanol and not by d-levorphanol are considered to be due to activation of the opiate receptor.
15 3. Certain compounds bind to the receptor but fail to activate it or only activate it partially. These compounds prevent the opiates activating the receptor and are therefore known as antagonists or, if they can weakly activate the receptor, as partial agonists/antagonists. The purest known antagonist is naloxone and drug actions which are blocked by naloxone are considered to be due to activation of opiate receptors.
Within the last five years it has become apparent that the opiate receptors exist because there are a series of natural compounds known as opioids, some of which are produced within the body and some of which are produced in the gut as a result of partial protein 974(:~
g dig~stion. There is strong suggestive evidence that these compounds are involved in schizophrenia and possibly in other disorders such as coeliac disease and psoriasis.
Using human platelets the inventor has been able to demonstrate that l-levorphanol but not d-levorphanol is able to block the formation of 1 series PGs from DGLA without blocking the formation of 2 series PGs from AA. The effect of l-levorphanol can be blocked by naloxone. The natural opioid, ~-endorphin, has an effect similar to levorphanol and this effect can also be reversed by naloxone.
Platelets from schizophrenics are known to produce very small amounts of P OE 1 from DGLA: nonnal platelets treated with l-levorphanol or ~-endorphin thus behave like schizophrenic platelets.
Thus:
1. Opiate drugs and opioids are able to block formation of P OE 1.
These effects can be reversed by opiate antagonists such as naloxone.
2. If one wants to ansure maximum formation of 1 series PGs from DGLA, especially in situations in which there may be endogenous opioids, DGLA should therefore be administered in conjunction with opiate antagonists such as naloxone.
The studies suggest that in diseases where there is overactivity of an opioid at some site, then opiate antagonists oppose this action and enhance the conversion of DGLA to PGEl. Such overactivity may be produced by excess amounts of a nonDal opioid, the presence of an abnormal opioid, or abnormal tissue sensitivity to normal ~97'.~LO

opioid levels. It is of interest that a natural defect of conversion of DGLA to PGE 1 in schizophrenic platelets can be imitated in normal platelets by incubation with l-levorphanol.
Therefore, in conditions in which it is desirable to increase formation o~ PGE 1 hy increasing intake of DGLA, GLA or their precursors, the effect is enhanced by opiate antagonists in situations where there is an excess of endogenous opioid activity.
Examples of such conditions include schizophrenia and coeliac disease. Opiate antagonists known per se and used clinically include nalorphine, levallorphan and naloxone but there is no restriction to these for use in the present invention. Naloxone, as a pure antagonist, is preferred.
MATERIALS AND METHODS
The detailed technique with platelets is given below by way of example.
(1- C) arachidonic acid and (1- C) dihomo-y-linolenic acid were used, diluted with hexane to specific activities of about 5~Ci/~mol. One day expired (2 days old) human platelets were obtained and used within 48 hours of expiration. One unit was centrifuged at lOOOg for 15 minutes and the supernatant drawn off.
The platelet pellet was resuspended in Tris-NaCl-~DTA buffer, made up of 0.15 M NaCl, 0.15 M Tris Hcl at pH 7.4 and 0.077 M NaEDTA
(90:8:2 v/v/v). The platelets we~e recentrifuged, the supernatant removed and the pellet resuspended in Krebs-Henseleit buffer (without calcium) at pH 7.4, The washed platelet suspension contained ~1~9740 about 1-2~ red blood cells. All glassware used in the preparation of the platelets was siliconi~ed.
Four equal sized 1 ml aliquots of the platelet suspension, containing 10 platelets/ml were incubated with e.g. 0.5 ~Ci 4C-DGLA for five minutes. At the beginning of the incubation the material under test was added to the suspensions. The reaction was stopped after five minutes by addition of 1/10 volume of 10% formic acid. The suspension was then extracted three times with ethyl acetate and the fractions pooled and dried under vacuum. The extract was then taken up with 5 ml chloroform/methanol (2/l,v/v).
Recovery of radioactive material in the extract was checked by taking 50 ~1 of the chloroform/methanol and counting by liquid scintillation. Recovery was in the range 80-95% in most experiments.
The chloroform/methanol extract was then reduced in volume to 1 ml under dry prepurified nitrogen. Thin layer chromatography was carried out on 500 ~g precoated, prescored silica gel G Vniplates (Analtech). Plates were activated by heating to loo& for 1 hour immediately prior to use. The solvent system was chloroform:methanol:
acetic acid:water (90:8:1:0~8). Reference compounds (PGs El and Fl and thromboxane Bl) were run at the same time and visualised by phosphomolybdic acid spray followed by brief heating. The bands on the plates corresponding to the reference PGE 1, PFG la and TXBl -were scraped off and eluted with 20 ml acetone. Each elution was then evaporated to dryness and counted by liquid scintillation tBeckman 100 LS counter).

, . . . . .. .. . . .

974~

Using the same batch of platelets at the same time exactly similar experiments were carried o~t with C-AA and PGE 2, PGE 2a and TXB 2 as reference compounds. Three experiments were performed with DGLA and three with AA.
RELATIONS~IP TO PREVIOUS PROPOSALS
The above approach may be used in combination with other materials as disclosed in the earlier patent applications of the inventor namely European Nos.79300079.5 and 79300546.3 (Publication Nos. 0 003 407 and 0 004 770: U.S. Serial Nos. 004 924 and 029 058).
Among these materials are a number believed to act by enhancing mobilisation of DGLA reserves,including zinc, penicillin and ~-lactam antibiotics generally, and also penicillamine, phenformin and levamisole when the other effects of these materials are acceptable.
Further~ since there is evidence that thromboxane A2 may indirectly enhance formation of PGE 1, substances such as colchicine, amantadine and melatonin, and also griseofulvin, vinblastine, vincristine and interferon as discussed in the pending patent applications and believed to act through increasing the production or effect of thromboxane A2, can also be used in conjunction with the materials of the present invention.
As appears from the earlier patent applications, in searching for ways to regulate PGE 1 formation the inventor has previously concentrated on the conversion of DGLA stores to free DGIA since this is believed to be a key rate-limiting step and since it has also been believed that factors which regulate conversion of free arachidonate to PGs will also regulat conversion of free DGLA to PGs. The present work has been more on the conversion of DGLA and of AA to the respective PGs, and as noted above, it has been found that the factors regulating the two PG pathways are in some respects quite different. The discoveries on which the present application is based however build on and add to the earlier inventions rather than superseding them.
~ According to the present invention there is provided a pharmaceutical composition comprising y-linolenic acid and/or dihomo-y-linolenic acid, optionally in association with linoleic or other fat acids, said acids being present as such or as physiologically functional ester or other derivatives, thereof, in combination with naloxone, nalorphine, levallorphan or other opiate antagonist.
DOSE RA _ES
The dose range for opiate antagonists is:
Naloxone - outer limits 0.1 to 500 mg/day for example orally or parenterally in four or six divided doses - desirable dose 10 mg to 200 mg/day Nalorphine - outer limits 1 mg to 5 g/day for example in divided doses orally or parenterally I`
- desirable dose 10 mg to 2 g/day Levallorphan - outer limits 0.2 mg to 1 gjday for example in divided doses given orally or parentally Dose ranges for materials auxiliary to those of the invention are discussed elsewhere herein. All the materials may be given in doses of for example one half, one third or one quarter of the above amounts.
The amounts are related to those quoted earlier for platelet and other experiments, though of course a precise relation cannot be given in view of variation in inactivation and excretion rates and 7~0 volume of distribution.
PACKS
If it is not desired to have compositions comprising the active materials together, as listed above, packs may be prepared comprising the materials presented for separate or part joint and part separate administration in the appropriate relative amounts, and such packs are within the purview of the invention.
VETERINARY APPLICATIONS
It will be understood that where a disorder of a kind callinq for treatment in animals arises, the invention while described primarily in terms of human medicine and treatment is equally applicable in the veterinary field.
AMOUNTS OF ACTIVE MATERIALS (ADJUNCTS TO PRESENT INVENTION) Amounts of materials are:
Zinc 2.5 to ~00 mg/day, preferably 10-80 mg calculated as zinc ~-lactam antibiotics 0.5 to 10 g/day Penicillamine 50 mg to 10 g/day Phenformin 10 mg to 5 g/day Levamisole 10 mg to 2 g/day Colchicine 0.3 to 15 mg/day, preferably 0.6 to 2.4 mg Melatonin 10 mg to 5 g/day ~mantadine 100 mg to 1000 mg/day Griseofulvin 0.5 to 5 g/day Vinblastine 0.5 to 5 mg/kg/week (average weight 70 kg) Vincristine 0.1 to 1.0 mg/kg/week (average weight 70 kg) Interferon (by injection) 1 x 10 to 1 x 10 units/day Detailed discussion of suitable amounts and fonms of use is contained in the published patent applications referred to earlier, to which reference may be made. In particular the B-lactam antibiotics are conveniently any of the known penicillin and cephalosporin antibiotics ~including semi-synthetic antibiotics) such as, for example, penicillin G, penicillin N, penicillin V, cephalexin, cephalothin, ampicillin, amoxycillin, cloxacillin and cephaloglycin. Any of these may be used in the form of their physiologically functional non-toxic derivatives, for example alkali metal salts e.g. sodium and potassium salts, and salts with organic bases, and reference to an antibiotic herein includesreference to such derivatives.
AMOUNTS OF y-LINOLENIC AND OT~ER ACIDS SPECIFICALLY
A preferred daily dosage for all purposes for an adult (weight ca 75 kg) is from 0.05 to 0.1 up to 1, 2, 5 or even 10 g as required of y-linolenic acid or equivalent weight calculated as y-linolenic acid or a physiologically functional derivative thereof. Amounts in particular may be 0.1 to 1.0 g daily. Corresponding doses of the Oenothera oil containing 8 to 10~ of y-linolenic acid, are easily calculated. In place of, or in addition to, y-linolenic acid, one may use dihomo-y-linolenic acid or a physiologically functional derivative thereof, in amounts equivalent in molar terms to y-linolenic acid and calculated as such. This dosage can for example be taken as a single dose or divided into 2, 3 or 4 sub-divisions thereof as convenient.

97~0 F~RMS AND SOURCE OF y-LINOLENIC AND OTHER ACIDS
Convenient physiologically functional derivatives of y-linolenic acid and dihomo-y-linolenic acid for use according to the invention for all the purposes described include the Cl-C4 alkyl (e.g. methyl) esters and the glycerides of the acids.
If desired, pharmaceutical compositions may be produced for use in the invention by associating natural or synthetic y-linolenic acid ~or a physiologically functional derivative thereof) and/or dihomo-y-linolenic acid tor a physiologically functional derivative thereof), as such, with an acceptable pharmaceutical vehicle.
It is at present convenient to incorporate the y-linolenic acid into compositions in the form of an available oil having a high ~-linolenic acid content, hence references to "oil" herein.
At the present time known natural sources of oils having a high y-linolenic acid content are few (there are no known natural sources of significant amounts of dihomo-y-linolenic acid).
One source of oils currently available is the seed of Evening Primrose species such as Oenothera biennis L. and Oenothera lamarckiana, the oil extract therefrom containing y-linolenic acid tabout 8%) and linoleic acid labout 72%) in the form of their glycerides together with other glycerides (percentages based on total fatty acids).
Other sources of y-linolenic acid are Borage species such as Borago officinalis which, though current yield per acre is low, provide a richer source of y-linolenic acid than Oenothera oil. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil ~1~9'7~0 source.
The seed oil extxacts referred to above can be used as such or can for exa~ple if desired be fractionated to yield an oily composition containing the triglycerides of y-linolenic and linoleic as the main fatty acid components, the r-linolenic acid content being if desired a major proportion. Seed oil extracts appear to have a stabilising effect upon any dihomo-~-linolenic acid or physiologically functional derivative thereof.
PHARMACE~rICAL PRESENTATION
The compositions according to the invention are conveniently in a form suitable for oral, rectal, parenteral or topical administration in a suitable pharmaceutical vehicle, as discussed in detail for example in Williams U.K. Patent Specification No. 1 082 624, to which reference may be made, and in any case very well-known generally for any particular kind of preparation.
Thus for example tablets, capsules, ingestible liquid or powder preparations, creams and lotions for topical application, or suppositories, can be prepared as required. Injectable solutions of hydrolysed Oenothera oil may be prepared using albumin to solubilise the free acid.
Advantageously a preservative is incorporated into the preparations. -Tocopherol in a concentration of about 0.1% by weight has been found suitable for the purpose.
It will be understood that the absolute quantity of active ingredients present in any dosage unit should not exceed that P7~0 - 18 ~

appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses. The rate of administration will moreover depend on the precise pharmacological action desired.
The following Examples serve to illustrate pharmaceutical com~ositions useful in treatment according to the invention:
EXAMPLES
Pharmaceutical compositions contain a unit dose of an oil extract from the seeds of Oenothera biennis L., and of one of the active materials of the present invention, optionally with methyl dihomo-y-linolenate and/or zinc oleate and/or penicillin V and /or any of the other active materials referred to herein directly or by cross reference to other patent applications of the inventor.
They may be presented by encapsulation of the natural oil in soft gelatin capsules by known methods.
The oil is extracted from the seeds by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed, or solvent extraction.
Fractionation of a typical sample of this oil shows a yield of 97.0~ in the form of methyl esters, with the relative proportions:

~14t97~

Palmitate 6.15 Stearate 1.6 Oleate 10.15 Linoleate 72.6 y-Linolenate 8.9 As preservative, -tocopherol is added to the oil in a concentration of 0.1%.
Gelatin capsules containing oil extracts prepared as described above, each having the following contents of active ingredients 10(0.5 g oil extract = ca 0.045 g y-linolenic acid), are prepared in conventional fashion.
The following are specific examples of capsules that may be given, two capsules three times a day, in treatment of the conditions listed earlier.

Oil extract 0.5 g Ascorbic acid 200 mg Naloxone 5 mg Two capsulec may be administered thrice daily in the treatment of disorders, giving a daily dose of y-linolenic acid of ca. 0.27 g.

Similarly to Example 1 the following may be administered:
Oil extract 0.5 y Zinc sulphate 10 mg Naloxone 5 mg ~1~97~0 -- ~o --_ PLF, Similarly to Example 1 the following may be administered:
Qil extract 0.5 g Zinc sulphate 10 mg Nalorphine 5 mg SimiLarly to Example 1 the following may be administered:
Oil extract 0.5 g Zinc sulphate 10 mg Levallorphan 5 mg Colchicine 0.2 mg It will be understood throughout that while a full theoretical discussion of what is believed to be the reason for the effectiveness of the compositions proposed is given to aid understanding, the invention is in no way to be limited by this discussion.
VALUE OF OIL + OPIATE ANTAGONISTS
In the platelet system l-levorphanol reduced formation of 1-series PGs, an effect abolished by naloxone and not shown by d-levorphanol. The concentrations concerned had no effect on production of 2-series PGs from AA. Thus if the levels of l-levorphanol used correspond to levels of natural opiates that are undesirably high, in which natural l-series PG production may be expected to be suppressed, use of naloxone may be expected to assist.
In the table below results are expressed as percentages of 37~0 control counts obtained without the drug and are the mean of three determinations:

Amcunt of PGE 1 TXBl l-levorphanol (precursor DGLA) 18 ng/ml 23~ 20%
18 ~g/ml 72~ 76~
It will be noted that an in~reased amount of l-levorphanol showed a reduced suppression effect. Such figures are frequently seen in PG work, higher concentrations showing a reduced or even reverse effect to lower concentrations.

Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition comprising .gamma.-linolenic acid and/or dihomo-.gamma.-linolenic acid, optionally in association with linoleic or other fat acids, said acids being present as such or as physiologically functional ester or other derivatives, thereof, in combination with naloxone, nalorphine, levallorphan or other opiate antagonist.

2. A composition as in claim 1, in dosage unit or other form comprising 50 mg to 10 g preferably 0.1 to lg of said .gamma.-linolenic or dihomo-.gamma.-linolenic acid or derivative (calculated as .gamma.-linolenic acid) together with respectively, 0.1 to 500 mg, preferably 10 mg to 200 mg; 1 mg to 5 g, preferably 10 mg to 2 g; 0.2 mg to 1 g, preferably 10 mg to 1 g, of naloxone, nalorphine or levallorphan or one half one third or one quarter of said amounts.

3. A composition according to claim 1 or 2, comprising further a material influencing the 1-series/2-series PG balance in the body in favour of 1-series PGs by enhancing conversion of DGLA
ester stores to free DGLA.

4. A composition according to claim 1 or 2, comprising further zinc, penicillamine, phenformin, levamisole, or a penicillin, cephalosporin or other .beta.-lactam antibiotic.

5. A composition according to claim 4 in dosage form comprising:

Zinc 2.5 to 800 mg/day, preferably 10-80 mg, calculated as zinc, or .beta.-lactam antibiotics 0.5 to 10 g/day, or Penicillamine 50 mg to 10 g/day, or Phenformin 10 mg to 5 g/day, or Levamisole 10 mg to 2 g/day

6. A composition according to claim 1 or 2, comprising further a material influencing the 1-series/2-series PG balance in the body in favour of 1-series PGs by enhancing the physiological production or effect of TXA2.

7. A composition according to claim 1 or 2, comprising further colchicine, amantadine, melatonin, griseofulvin, vinblastine, vincristine or interferon.

8. A composition according to claim 7 in dosage unit form comprising:
Colchicine 0.3 to 15 mg/day, preferably 0.6 to 2.4 mg, or Melatonin 10 mg to 5 g/day, or Amantadine 100 mg to 1000 mg/day, or Griseofulvin 0.5 to 5 g/day, or Vinblastine 0.5 to 5 mg/kg/week, or Vincristine 0.1 to 1.0 mg/kg/week, or Interferon 1 x 105 to 1 x 108 units/day