WO1982003986A1

WO1982003986A1 - Medicinal composition

Info

Publication number: WO1982003986A1
Application number: PCT/GB1981/000091
Authority: WO
Inventors: Alfred Jenkinson
Original assignee: Alfred Jenkinson
Priority date: 1981-05-21
Filing date: 1981-05-21
Publication date: 1982-11-25
Also published as: AU7172381A; EP0079329A1

Abstract

A composition e.g. for the treatment of arthritis comprising in combination a short-acting barbiturate soporific and a non-hormone antipyretic agent having a specific activity greater than aspirin. The preferred barbiturate comprises sodium amytal. The preferred anti-inflammatory agent comprises phenylbutazone.

Description

MEDICINAL COMPOSITION

The present invention relates to a medicinal composition.

My. British Patent Application Serial

No. 2062458 due to be published on 28th May 1981 describes and claims a composition for the treatment of arthritis and associated rheumatic diseases. The composition is described as of proven benefit in the treatment of osteoarthrosis but may also be beneficial in cases of rheumatoid arthritis, ankylosing spondylitis, gout, Raynaud's diseas, Paget's disaese,

Felty's syndrome, systematic sclerosis, erato conjunctivitis, Still's disaese, chrondro-calcinosis and hydroxiapatite deposition.

I have now found that the original composition of Application 2062458, with some optional modification, is effective in a wide range of disorders.

The present invention therefore includes the invention described and claimed in the said Application Serial No. 2062458 and extends the use of the composition to other disorders. The invention is first described in relation to the treatment of arthritis disorders.

Very little is still known about the causes and effective treatment of- such diseases and many of the treatments currently in use lead to very serious side effects which indeed can produce symptoms more debilitating than the original disease. Typical treatments are with antipyretics such as phenylbutazone (4 Butyl-1,2-diphenyl- pyrazolidine-3,5-dione. Otherwise l:2-diphenyl-3:5-dioxo- 4-n-butyl-pyrazolidine) , gold compound injections, and treatment with hormone drugs such as cortisone^ Large quantities of aspirinare often administered. The long term _{use 0}f steroid drugs related to cortisone gives rise to very serious side effects such as peptic ulcers, fattening of the face and other regions, disorders of the body's sugar mechanism with a tendency to induce diabetes, mellitis and osteo porosis which can lead to fracture of the bones and deformation of the spine.

Rheumatoid arthritis is a very serious condition although it is seldom listed as the cause of death. Sufferers are known from statistics to have a low life expectancy and usually lead a miserable existance from the onset of the disease until death. A major difficulty is that the drugs being administered often have only a transitory effect, so that greater and greater doses .are administered over long periods of time so that the side effects become pronounced. Drugs having serious side effects -could be tolerated in the treatment of arthritis if an immediate alleviation of a permanent nature could be ensured.

The invention is based upon the original discovery that by combining two drugs having different effects, a permanent alleviation of quite serious conditions of arthritis can be effected. The two drugs involved are a short-acting soporific and an antipyretic which should not be of the hormone or steroid type. More specifically in accordance, with the invention there is provided a composition comprising in combination a short-acting barbiturate soporific and a non-hormone antipyretic agent having a specific activity greater than aspirin.

The preferred barbiturate is sodium amytal (sometimes called amobarbitol, monosodium isoamyl ethyl barbiturate). This compound has the formula:

CO

Sodium amytal is currently seldom prescribed. It is a very powerful short term soporific, producing a quiet sleep with no ataxia or disagreeable after effects and is described in U.S. Patent No. 1 ,514 ,573. It does ,

S t howeveα*, have habit forming properties and has been shown to cause cancer if given in very large quantities . It may be replaced by other equivalent barbiturate drugs of similar short term effect, a number of which are known. The preferred antipyretic is phenylbutazone as mentioned above, which is a common antipyretic, large quantities of which are used in the veterinary field. Its effect alone in the treatment of rheumatoid arthritis is comparatively weak and transitory as normally administered. The compound is described in U.S.

Patent No. 2 ,562 , 830 and British Patent^' No. 812 , 449. Other pyrazolidine antipyretics as described in the said U.S . patent may be substituted, e. g. the ^-cyclohexyl- derivative and the 4-n-propyl- and 4-isopropyl- derivatives of 1 :2-diphenyl- 3 :5-dioxo— pyrazolidine, and indeed more recently developed equivalent antipyretics notably of the pyrazolidine "type. The composition may also comprise a quantity of a soluble form of aspirin, and preferably also an ingestible form of ethyl alcohol. The aspirin is believed to agument the antipyretic effect and the alcohol accelerates the uptake of the drugs into the bloodstream. An equivalent dose of paracetamol may be substituted.

Preferably also the composition includes or is taken with a quantity of soda water. The composition may include a sweetening such as saccarin or a cyαlamate but should preferably not. contain any sugar. It may include ginger or other taste modifying agent.

A preferred form of the composition may consist of:- phenylbutazone - 1 to 2 parts sodium amytal - 1 to 2 parts ingestible ethyl - 4000 to 6000 parts alcohol the balance including water together, optimally, with a non-sugar sweetening agent and/or taste modifying agent.

The balance may include soda water and ginger. A suitable single dose would be 200 mg phenyl¬ butazone and 200 mg sodium amytal, together with 60 ml of a 65 or 70% proof spirit e.g. Scotch whisky or brandy diluted in an

OMPI appropriate quantity e.g. 60 ml of soda water or diet giner ale.

Such a dose suitably follows a dose of 900 mg soluble aspirin B.P.- or 650 mg paracetemol taken in •su ficient water to disolve the compound.

The composition may be sold in the form of a multiple dose elixir-. A suitable 10 dose elixir is as follows:—

Elixir_I phenylbutazone 2 g. sodium airytal - 2 g. medicinal brandy or whisky - - 600 ml. ginger concentrate - 10 ml. to be drunk 1:1 to 1:2 with soda water.

If desired the aspirin may be combined in the elixir as follows:— Elixir_II (10 dose)

soluble aspirin B.P. 9 g. phenylbutazone 2 g. sodium amytal 2 g. water (containing the aspirin) 20 ml. medicinal brandy or whisky - 600 ml . to be drunk 1 : 1 to 1 :2 with soda water. To reduce any possible after effects e.g. of the alcohol, some vitamin C may be incorporated.

The composition may alternatively be sold in the form of readily dissolving tablets containing citric or tartaric acid and sodium bicarbonate. Such tablets could readily include the aspirin component and could be dissolved in an appropriate amount of a proprietory alcoholic liquor, appropriately diluted with water or soda water or e.g., diet ginger ale. The effect of the composition is hereafter illustrated by reference to a clinical history. EXAMPLE 1 - Treatment of arthritis ,

The patient at the periods in.question was an active man in his 60's who had been treated on a number of occasions for osteo arthrosis in one of the joints in the cervical region of the spine and also with a weak disc in the sacral bottom which had been relieved from time to time by treatment with phenylbutzone and distalgesic, together with soluble aspirin. The drugs relieved the condition adequately although it recurred from time to time.

At age 61 the patient damaged his right knee by kicking a football. Within ten days of the incident the knee was swollen and painful and inflamed. About two months after the incident the patient visited his physician, at which time both the knee and lower leg were swollen and inflamed and resembled a thrombic condition the patient had had some years earlier. The physician arranged for examination by a vascular i expert who however diagnosed osteo arthrosis'in the knee which was confirmed by an X-ray. Examination by an arthritis specialist was delayed for six months.

By this time the knee was very inflamed and painful and the patient was partially lame and using a stick. He had .only restricted use of the right leg as a result of a popliteal cyst behind the knee which tended to press on the sciatic nerve centre when the knee was flexed. This caused intense pain and spasming (cramp) in the muscles besides inflammation and swelling. The treatment prescribed was physiotherapy which the patient attended twice weekly for 4 weeks. After each treatment the leg became more inflamed and eventually the patient refused further treatment. Soon after the whole leg went into spasm and the patient was virtually immobile. The patient was admitted to hospital where a diagnosis was osteo arthrosis in the knee accompanied by a marked very hard popliteal cyst behind the knee,

\ infiltration of the synovial fluid through the soft tissues of the lower leg causing general swelling as far as and including the ankle joint. The patient was released after a night in hospital and later attended a -Rheumatologist who confirmed the original diagnosis and administered a cortisone injection into the knee cavity and prescribed 200 mg of phenylbutazone every night. The injection eased the pain immediately but wore off within 2 days. The phenylbutazone gave temporary ease but no permanent alleviation of the condition and the patient was led to expect an excision of the cyst and a partial o total synovectomy of the knee, which he realised would be a long treatment with a debilitating end result. The patient at that point tried a number of drugs in various combinations. The final treatment attempted was to take 900 mg of soluble aspirin B.P. in sufficient water for dissolution and followed by 200 mg phenylbutazone and 200 mg sodium amytal taken with 60 ml of Scotch whisky and 60 ml of diet ginger ale as a stomachic medicine. Sugar was avoided to avoid increasing the output of uric acid.

The patient attempted this first dose about one month following the treatment by the Rheumatologist.

The patient immediately went to sleep and awoke 7 hours later feeling well. Upon examining his right leg he could see and feel and remarkable improvement. The swelling had subsided and the knee joint was freer and the cyst no longer pressed on the sciatic nerve, and the inflammation was generally reduced. .There was no constipation. The patient repeated the dose nightly for 7 further nights, after which all swelling had subsided and there was no more inflammation. The popliteal cyst was still evident but under no pressure .so that it was evident that excess fluid was no longer forming. In all, the

* patient took 23 doses after which he went for a holiday, feeling much improved and was able to jog and walk swiftly for one mile on the beach everyday and to swim.

There was no sign of arthritic inflammation in the knee. The patient paid three visits to the .Rheumatologist and after the last visit, some two months after the first dose* the patient was discharged. Five months later there had been no further occurrence of the arthritic condition.

*After the first 7 days, no further aspirin was taken. It can be appreciated that the preferred composition as represented in the Example can lead to a complete recovery at least in certain cases of osteo arthritis. Since the treatment, if successful, is of short term, the danger from side effects is negligible and in any case the side effects from the preferred drugs are maxkedly less than those associated with e.g. steroids. Furthermore the long term effects of the drugs concerned are not a factor provided that the composition is used as advocated for a short treatment period.

I have now found that the composition described above in relation to the treatment of arthritic diseases probably has much wider application. More specifically:

1. the composition has been found useful in promoting growth of healthy tissue.

2. It is believed to act through the blood stream in countering cancerous process.

3. It has been shown^"to provide an effective and rapid cure for influenze, common colds and allied viral disorders.

4. It is proposed for the treatment of congenital diseases involving gene mutations.

EXAMPLE 2

Promotion of Healthy Tissue

(a) The patient described in the first Example," after the first alleviation of his arthritic condition, became engaged in an undue athletic activity and this aggrevated his old condition of the left hip which had been arthritic .for some years but only gave spasmodic relatively minor discomfort. Excessive inflammation was caused due to a sharp rise in the RH factor in the synovial fluid. He began using the treatment of Example 1 for the second time and obtained instant relief. One dose removed discomfort and pain for 72 hours. Since both cartilage and joint bone formation were already damaged, no permanent cure was likely other

than surgical removal of the boney osteophytes or the fitting of an artificial hip.

A visit to a leading osteopedic surgeon confirmed that the hip joint was in an advanced stage of disintegration but an operation was not recommended since the current operative technique was proving unsatisfactory at the time. The patient was told to wait for a period of two years.

The patient then resumed the previous treatment with the composition of the invention. Contrary to all expectation, as treatment continued with two doses a week the condition of the hip got better and better.

It appeared that the treatment was causing a change in the synovial fluid which reversed the arthritic chain. It furthermore appeared as though healthy tissue was being built-up.

The patient, after giving up the treatment is sufficiently active that recourse to surgery may be avoided.

' The above patient, having noticed the effect of the medicine upon the healing process in general, tested it out on the following other occasions.

(b) On two different occasions, burns caused by different operations healed in less than three days as against a normal expected healing period of ten to fourteen days. Furthermore, after initial healing, the period when the new healthy tissue was bright red was greatly reduced so that disfiguration was minimal. This may have important aspects in cosmetic surgery. In each^' case one dose as described in Example 1 was taken on each of two successive nights.

(c) The patient has a weakness in the mucuous skin on his top lip which tends to peel off after drinking overheated liquids. On each occasion one dose was taken for successive nights. There was a noticable improvement after the first might and a virtual cure in two days.

(d) The same patient fell headfirst down a flight of concrete steps, sufferent severe concussion, slight brain damage resulting n damage to both eyes (cataracts) , a partially dislocated right shoulder joint and torn adjacent ligaments and severe lacerations to the right side of the head above the ear. Healing to head was slow during the patients four days as an in-patient at a general hospital. When the patient returned home after the four days, he took a dose of the medicine described in Example 1. The next day the wound in the head had skinned over and by the time he went to see the consultant -surgeon three days later, all the scabs had gone and the new tissue was only slightly pink. The surgeon commented upon the patients remarkably quick healing power.

(e) The patient when swimming in the sea was carried over a submerged wooden groin resulting in a badly scraped thigh from barnacles. The skin was removed over about four square inches. Two doses of the medicine of Example 1 were taken one on each of two successive nights. Within two days the wound had skinned over with thin tissue and there are no lasting blemishes.

EXAMPLE 3

Treatment of Influenza

Two patients contracted influenza from respective relatives who had been bed-ridden through the disease for some two weeks. A single dose of the composition as prescribed in Example 1 effectively controlled the disease to the extent that the patient was up within 72 hours. Temperaturesof over 10l°F (30.8 C) were bought down to normal within 36 hours.

' EXAMPLE 4

Treatment of Circulatory Disorders

The same patient has suffered from associated blood circulation disorders since 1967. He has had four major thrombic attacks: in 1957 thrombosis of the left leg; 1953 minor coronary; 1967 thrombosis of the right •f leg; 1975 serious major thrombosis of the right leg as a result of which he was treated with warfarin for eighteen months.- Until the patient started taking the medicine as described in Example 1 for an arthritic condition he had very bad varicose veins in both legs. Because of the patients tendency to form blood clots he was advised not to undergo surgical stripping when he enquired in about 1976. Since taking the medicine for the arthritic condition already described and on other instances, the varicose veins in both legs virtually disappeared.

DISCUSSION

It is apparent that the Examples above show that the composition of the invention not only is effective in the control of arthritis but has an effect beyond this. It appears to act through the blood stream and repair damagedtissue through this process. Clearly if this ability can be brought out by further trials, it is likely to be useful in a wide range of medical disorders, notably in reversing the development of cancer if this is caught at a very early stage, through the process of repairing mutated cells in the blood stream before they reach a "rogue" condition. It has now become possible through the use of scanners to show cancerous conditions at a sufficiently early stage for this process to be applicable.

While the effects of the composition of the invention became apparent to the inventor through a series of fortuitous circumstances, backed up by scrupulous and intense observation, the following comments may serve to assist a better understanding of the mechanism of the healing process. However reliance is not based upon these observations as regards the scope of the invention.

It is believed that the composition acts by an accelerated healing process both within the bloodstream and by accelerated action upon the adjacent tissues as a result of the healing conditions brought about within the blood stream. This healing process is believed to be a syndrome of a number of factors, the two most notable being a catalytic effect upon the repair of damaged cells and the various bodily effects caused by a complete reduction of hypertension. The reduction of hypertension intimately associated with relief of inflammation at the wound location, with the possible addition of electrolytic catalysis of the repair mechanism are believed to be the critical contributory factors.

It is now known that electrical charges play an important part in the binding forces within the cell structure. Mutation can result in the separation of the .&mino acid chain into charged fractions, often leading to the abnormal growth of one part of the broken chain. This can cause separation of the DNA and RNA factors or their subjection to chemical and probably electrolytic changes which can affect the whole regular pattern of growth and also the chemical nature of the cells themselves. If the 'controlling DNA factor is out of control, the remaining protein development can stimulate all adjacent cells until the originally mutated or "rogue" cell becomes a cancerous growth. This illustrates that repair of the damage at an early stage within the bloodstream is of fundamental importance. Later methods of treatment such as X-ray and lazer bombardment can only have a limited effect. Furthermore, it is now largely accepted that drugs which act on the body's i uno- suppressive system such as steroids can do more harm than good by their suppressive action upon therapeutic factors within the system.

It is believed that the composition of the invention acts by rectifying damage caused at an early stage within the bloodstream and by stimulating natural therapeutic factors.

A blood plasma catalyst appears to be present which assists in bringing healing factors to target areas. The sodium ion is known to be a powerful blood catalyst and the sodium ion is a factor of importance within the composition of the invention, being present in one of the preferred compounds, sodium amytal and also in soluble aspirin. The choice of sodium amytal is also influenced by the knowledge that this short to medium acting soporific leads to residues (metabolised) which are easily excreted by the kidney. Likewise, from a study of the passage of drugs through cell membranes and the desirability of promoting active transport to accelerate the healing process, alcohol is selected. This can allow the drug to cross membranes even against concentration gradients. The concentration of sodium may require careful monitoring since it is known to be a natural constituent of full blood plasma and its addition can lead to undesirable ion gradients.

The action of aspirin, a preferred ingredient, may be of importance in its effect in stimulating the lymph glands so speeding up the production of lymphacites and increasing the body's natural resistance towards pathogens. The increased ionic concentration may be an assisting factor in binding disrupted cells and other

organic compounds essential to life, notably hormones and enzymes. Jhe sodium ion may also contribute by speeding up the oxygenation process and reducing the tendency to the formation of blood platelets, so smoothing and speeding the passage of the mixture through the blood to the target area. Although the sodium ion present in two possible ingredients may be of great catalytic importance, it is believed that the combination of the anti-inflammatory agent and soporific is critical. The anti-inflammatory agents have had a generally disappointing history in human medicine,, and the same can be said to be true of soporifics. The reverse is possibly true in the veterinary -field where the inhibiting actors to their use do not play such an important part. Thus phenylbutazone is widely used and an understanding of its properties has been greatly increased. Likewise it is quite common in the veterinary field for almost miraculous results to be obtained merely by the induction of deep sleep and total relaxation and reduction in hypertension. The development of such treatments in human medicine has been inhibited largely by fears of the long term action of the most appropriate drugs.

By means of the invention which selectively combines the necessary action, it is believed that the healing process can be so accelerated that long term effects can be neglected. In effect the action of the one drug reinforces and accelerates the reaction of the other, possibly assisted by ionic catalysis in producing results which are completely unexpected in human clinical f practice.

The eventual control and elimination of major diseases is likely to be found in (a) early detection and

(b) . an understanding of the genetic code and the purpose and identification of individual genes and chromosomes and the whole body-building sequence of^" amino acid chains, their linkages and the electrolytic charges associated with them. Once this is fully understood it will become possible to not only control disease but to synthesise the proteinsessential to life which a patients body cannot produce metabolically.

It is believed that the composition of the invention assists in the repair of elementary healthy building blocks within the bloodstream and in particular may assist in the healthy production of DNA and RNA which assists the body to build-up healthy tissue and destroy faulty cells. Speed of healing is a fundamental contributing factor since the treatment cannot be recommended over a long term, mainly due to the side effects of the prolonged usage of various of the ingredients. Nevertheless where the disease warrants - 12 -

more prolonged treatment, it is believed that this could be beneficial, particularly in the treatment of arthritis. For example a dose as prescribed in Example 1 could be used on alternative nights for sixty to ninety days with 5 extreme benefit to semi-crippled patients who would normally be housebound, enabling them to reach a sufficiently active stage to pursue a normal life.

The projected possible benefit of the invention in assisting the healthy production of DNA and RNA

--^Q which assists the body to build up healthy tissue and destroy faulty cells, may have benefit in the treatment of certain congenital diseases caused by the inheritance of faulty genes or cells. This might include certain mental disorders.

15 In summary the invention provides a medical composition comprising in combination a short-acting barbiturate. Soporific e.g. sodium amytal, and a non-hormone antipyretic agent having a specific activity greater than aspirin, e.g. phenylbutazone.

20 ^τh^e composition is proposed for a wide range of disorders and notetably for administration to humans or animals:

1. For the treatment of arthritis.

2. FOr use in promoting growth of healthy 25 tissue. 3. For use in countering cancerous processes in the bloodstream. ^{•' •}

4. For use in the treatment of influenza, common colds and allied viral disorders. 5. For use in the treatment of congenital diseases involving gene mutations.

Φhere is also provided in accordance with the invention a process for the treatment of humans or animals which comprise the administration of one or more effective doses of the composition of the invention, for the purpose of correcting the disorders specified above.

Claims

1. A medicinal composition comprising in combination a short-acting barbiturate soporific and a non-hormoiie antipyretic agent having a specific activity greater than aspirin.

2. A composition according to claim 1 wherein the barbiturate comprises sodium amytal.

3. A composition according to claim 1 or claim 2 wherein the an i-inflammatory agent comprises phenylbutazone.

4. - A composition according_.to any preceding claim wherein the anti-inflammatory agent also comprises a soluble aspirin.

5. A. composition according to any of claims 1 to 3 wherein the anti-inflammatory agent also includes paracetamol.

6. A composition according to any preceding claim including ingestible ethyl alcohol.

"BURE

7. A composition according to claim 1 consisting of:

phenylbutazone - 1 to 2 parts sodium emytal - 1 to 2 parts ingestible ethyl alcohol - 4000 to 6000 parts i

the balance including water together, optionally, with a non-sugar sweetening agent and/or taste modifying agent.

8. A composition according to claim 7 wherein said balance includes soda water.

9. A composition according to any preceding claim involving an ionizable sodium compound.

10. A composition according to any preceding claim for use in the treatment of arthritis.

11. A composition according to any of claims

1 to 9 for use in promoting growth of healthy tissue.

12. A composition according to any of claims

1 to 9 for use in countering cancerous processes in the bloodstream.

13. A composition according to any of claims

1 to 9 for use in the treatment of influenza, common colds and allied viral disorders.

14. A composition according to any of claims 1 to 8 for use in the treatment of congenital diseases involving gene mutations.

15. A process for the treatment of arthritis in humans or animals which comprises the administra¬ tion of one or more effective doses of a composition according to any of claims 1 to 9.

16. A process of treatment for promoting the growth of healthy tissue in humans or. animals which comprises the administration of one or more effective doses of a composition according to any one or claims 1 to 9.

17. A process of treatment for humans or animals for countering cancerous processes in the bloodstream which comprises the administration of one or more effective doses of a composition according to any one of claims 1 to 9.

18. A process for the treatment of influenze, common colds and allied varial disorders in humans or animals which comprises the administration of one or more effective doses of a composition according to any one of claims 1 to 9.

19. A process for the treatment of congenital diseases involving gene mutation in humans or animals which comprises the administration of one or more effective doese of a composition according to any one of claims 1 to 9.