~(1876~a BACKGROUND OF THE INVENTION
Sulfurized polyunsaturated oils, or sulfurized oils, are disclosed in a book entitled RESEARCH IN PHYSIOPATHOLOGY AS
BASIS OF GUIDED CHEMOTHERAPY by Emanuel Revici, M.D., publis- -hed by D. Van Nostrand Company, Inc., 1961, pages 334 and 335.
- A method of preparing sulfurized polyunsaturated oils referred to in the book as hydropersulfides is set forth in Note 7, page 711 of the book. This book does not disclose the use of the sulfurized compounds for treatment of alcoholism nor the specific compositions disclosed and claimed herein.
SUMMARY OF THE INVENTION
The invention relates to a method of treating alcoholism and for preventing or reducing alcohol intoxication in humans by administering thereto a sulfurized polyunsaturated oil. The invention is also directed to such sulfurized polyunsaturated oil compositions. The sulfurized polyunsaturated oils (hydro-persulfides) can be administered to the patient by the various known methods of injection or orally in capsule form.
STATEMENT OF THE INVENTION
The invention as claimed herein is a method of making a sulfurized polyunsaturated oil or fatty acid therapeutic com-position suitable for treating alcoholism or for eliminating or preventing alcohol intoxication which comprises mixing sul-fur with a polyunsaturated oil and heating the mixture over a prolonged period of time with stirring while introducing air into the mixture, to a temperature above about 90C. and below about 130C. for a period of time sufficient to react or com- -bine with the sulfur.
The unsaturated oil is preferably sesame oil. The heat-ing time and the amount of sulfur used is preferably sufficient to produce a sulfurized polyunsaturated oil containing at .. . .. . . .
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least about 0.1~ by weight of sulfur based on the weight of the oil. The reaction mixture may be cooled to room temperature and sulfurized oil containing crystals is precipitated out dur-ing the cooling step and the liquid is then separated from the sulfur crystals. A portion or all of the sulfur crystals may be placed back into the liquid and permitted to dissolve there-- in, slowly.
DETAILED DESCRIPTION OF THE INVENTION
Various polyunsaturated fatty acids or oils or triglycer-ides can be used to react or combine with sublimed sulfur to form sulfurized oil according to this invention. These poly-unsaturated fatty acids constitute a well known class of com-pounds and includes such fatty acids as sesame oil conjugatedlinoleic acid, conjugated eleostearic acid, cottonseed oil, and mixtures of fatty acids obtained from such sources as cod liver oil, fish oil, etc.
The sulfur used to form the sulfurized oils is sublimed sulfur, sometimes referred to as flower of sulfur, that is, sulfur which is produced by sublimation or by the sublimation of elemental sulfur. Sublimed sulfur is available on the mar-ket at most chemical stores.
The sulfurized oils or fatty acids can be prepared byadding the sublimed sulfur to the oil, such as sesame oil, and - la -87~J~i3 , heating the mixture with agitation at a temperature not to exceed about 130C. It is preferable or advantageous to heat the mixture between 120 and 127C. Heating the mixture above about 130C.
causes a progressive color change in the mixture and otherwise appears to be detrimental. The temperatures given above relate to the reaction of the sublimed sulfur with sesame oil. The ranges of temperatures which can be used to produce the sulfurized oil may vary with the particular oil being used, but generally a temperature of 120C., preferably 125C to 127C, will be sufficient for most oils.
If the oil and sulfur is heated below about 90C, it is difficult to incorporate the sulfur into the oil by heating and stirring alone. The best results have been obtained to date by maintaining the temperature used in forming the sulfurized oil over a prolonged period of time from about 30 minutes to one hour.
Stirring aids in the reaction, and experiments to date indicate that a fairly violent stirring by introducing air into the mixture during the heating is preferable, particularly when the mixture is not subjected to prolonged heating.
After the reaction has taken place, it is cooled.
Generally, depending on the amount of sulfur used, some sulfur crystals remain in the bottom of the reaction vessel which can easily be removed by filtration. The remaining fluid is ready for use after appropriate sterilization for injection or incorporated into capsules, such as gelatin, for oral administration. ~-It is sometimes advantageous to take some of the crystals remaining which have been separated from the fluid and place them back in the fluid obtained to increase the sulfur content. These crystals slowly dissolve in the solution. It is preferable that all crystals be dissolved prior to the use of the fluid when inje~ted into the host.
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The amount of sulfur incorporated into the oil is advantageously be-tween about 0.1~ to 2.5% by weight, based on the oil. Higher amounts of sulfur can be used; however, there appears that there is no advantage to doing so since the ultimate dosage given to the patient is the criteria rather than the amount of sulfur content in the oil. The amount of sulfur combined with the oil can be as high as at least 4-5%, for example, but to date there appears to be no advantage in using higher amounts of sulfur above about 1% to 2.5~.
As can be observed from Example 2 below, the incorporation of the sulfur into the oil seems to be limited to about 1% by the process presently being used to produce the sulfurized unsaturated oils. This sulfur content can be increased by re-adding the precipitated sulfur crystals, which are saturated with the oil, back into the solution. Some of these crystals will slowly dissolve to increase the sulfur content. When following this procedure, it is advantageous to reduce the size of the crystals having oil ~ -therein by stirring during cooling to obtain micro crystals and incorporate these micro crystals into the solution. A composition in which all of the added crystals do not dissolve can be encap-sulated and administered orally.
The sulfur content can be much less than about 1~ if desired and smaller sulfur content is advantageous when adminis- --tered by injection as discussed below. Varying the amount of sulfur below about 1% in the sulfurized polyunsaturated oils for oral administration only affects the number of capsules to be taken at a given time by a particular patient.
Experiments to date indicate that the optimum sulfur ~-content for oral administrations is about 1% and by injection about 0.1% to 0.3~ by weight of the sulfur based on the weight of the oil.
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The dosage prescribed to a patient will, of course, vary depending upon the particular patient and the purpose for which he is being treated. For an alcoholic, for example, it is advantageous for the patient to take 5 capsules containing 1 ml of the sulfurized oil containing about 1 to 2% sulfur for the first 3 days and take 3 or 4 capsules a day for the next 4 days. This is generally suffi-cient to eliminate or reduce the desire or need for alcohol. The desire or need for alcohol generally disappears from the patient within 24 hours. This single treatment may last for months. How-ever, the patient can be given an additional supply of the encap-sulated sulfurized oil and directed to take a capsule if he feels any desire or need fox alcohol.
When the sulfurized oil is used by injection, such as intermuscularly or intraperiotoneally, it is advantageous to have the sulfur contained in the sulfurized oil below about 0.5% by weight, preferably between about 0.1~ to 0.3~ by weight, and to inject from 1/2 to 3 ml of this solution into the patient. Experiments to date indicate that the injection of sulfurized oil is somewhat painful when it contains above about 0.5~ sulfur. Administration by ~
injection is, of course, not necessary, but it may act faster ~;
initially. Generally if a person is given the injection of the sulfurized oil, he can also be given a supply of the oral capsules and directed to take 3 to 4 capsules a day following the injection for one week.
To eliminate or reduce àlcohol intoxication, the patient is directed to take 2 to 5 capsules. The alcohol intoxication (containing 1 ml oil at 1% sulfur) should generally disappear within 20 minutes to one-half hour.
To prevent alcohol intoxication 1 or 2 capsules (containing 1 ml oil at 1% sulfur) can be taken prior to beginning consumption of the alcohol or with the first drink.
A sulfurized oil was prepared by mixing 50 grams of .:
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sublimed sulfur, obtained from Eisher Scientific, with one liter of sesame oil. The mixture was heated under fairly rapid agitation by air to a temperature of abou; 127 C until all of the sulfur was incorporated into the sesame oil. The reaction mixture was then cooled to room temperature, producing at the bottom of the reaction vessel a small amount of sulfur crystals.
The crystals were then separated from the liquid by filtration and about half of the crystals replaced in the resulting liquid, wherein they slowly dissolved.
The resulting sulfurized oil was then incorporated into gelatin capsules in the amount of l ml per capsule.
A 50-year old patient, s.G., reported that he had been an alcoholic for 20 years consuming up to l/5 to l/2 gallon of hard liquor a day. The patient reported that he had tried hospitaliza-tion and different treatments without success. The patient was given 5 of the above capsules the first day and directed to take 5 capsules on the second and third days and 3 capsules for each of the 4 days remaining in the week. The patient reported no desire for alcohol after the first day and felt no need or desire for 20 alcohol thereafter. The patient reported that he was feeling exceptionally fine.
4 g. of sulfur were weighed out and placed in an Erlin-meyer flask. 200 ml of sesame oil were added; the contents were heated to 125 C with stirring until the sulfur dissolved. The flask was removed from heat and allowed to cool to room tempera-ture (5 hours). Sulfur crystals were filtered into a Buchner funnel, washed thoroushly with hexane to remove residual oil, and weighed.
The above example was repeated 3 times. The washed sulfur precipitate was weighed in each trial and the amount of sulfur in the sesame oil calculated by difference as follows:
Initial weight of sulfur: 4.00 g; Weight of sulfur ppt.:
r ~ Trial l: 2.05 g; Trial 2: 2.00 g; Trial 3: 1.92 g.
i ~ -5-% (w/v) sulfur in sesame oil:
Trial 1 1.02 Trial 2 1.00%
Trial 3 0.96%
From this it was concluded that the solutio~ contained approximately 1% sulfur after filtration.
Using the composition as prepared in Example 2, a study was made to determine the effects of administration of these compositions to rats to see if they would voluntarily modify the rats' comsumption of alcohol.
The rats chosen for the study were Cobs rats obtained from the Charles River Breeding Laboratories, Inc. of Wilmington, Massachusetts.
Two cages with 5 female rats each and two cages with 5 male rats each were exposed to the same daily measure of pure drinking water, water with 8~ ethanol, and rat chow (Purina).
Two other cages, one containing 6 female rats and the other 6 male rats were given the same daily measure of the same rat chow and "
pure drinking water, but no ethanol solution. These cages not given the ethanol choice were maintained for control purposes.
After 23 days of exposure to the choice of the drinking water and ethanol solution, all four of these cages demonstrated an acceptance of and steady comsumption of the ethanol solution.
Intervention into the rat chow diet of a randomly chosen female cage and a randomly chosen male cage, exposed to the choice of pu~ drinking water and the~thanol solution, was made with 1 ml of the composition of Example 2 per 100 gms of the rat chow, (Groug A). The remaining 2 cages (Group B) were left unchanged.
Daily measures of water, ethanol solution and feed consumption were recorded on a per-animal basis on the Group A and Group B rats and on the control (Group C) which received no ethanol solution. -~
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It is first pointed out that the weight gains, feed consumption and ethanol consumption during the period prior to the introduction of the composition of Example 2 in the feed of the Group A rats was very uniform, and the progress graphs for each cage proceeded in almost an identical manner in both Group A
and Group B rats until the intervention of the composition of Example 2 in the feed of the Group A rats.
During the 23 days acquisition period, the rats in both Groups A and s developed a steady drinking habit of the ethanol solution and the consumption of the alcohol in Groups A and B, near the end of the period, was almost identical. Both Groups A and B rats were averaging about 22 ml per rat per day of the ethanol solution. Immediately after the introduction of the composition of Example 2 in the feed of the Group A rats, on the 24th day, a clear and substantial voluntary drop in ethanol consumption occurred in the Group A rats. During the 8th and 9th days after the intervention of the composition of Example 2 into the Group A rats, they were averaging only 10.5 ml of the ethanol solution. The average drop in ethanol consumption in the Group A
~20 female rats was 12 ml per rat per day and is statistically significant. The drop observed for the male rats in Group A was 8 ml per rat per day and is also statistically significant. The female drop is higher simply because they exhibited a substantially higher capacity for the ethanol solution.
No specific procedures were used to attract or distract the rats to the alcohol solution or to decrease their attraction once they were drinking.
There were no side effects observed by using the com- -position of Example 2 and all animals survived and had a growth rate as predicted by the Charles River Breeding Laboratories, Inc.
The experiment clearly demonstrates that the compounds of Example 2 cause rats to voluntarily decrease, in a substantial amount, their consumption of ethanol.