US3790682A

US3790682A - Ataractic use of dimethyl sulfoxide

Info

Publication number: US3790682A
Application number: US00093841A
Authority: US
Inventors: R Herschler; S Jacob
Original assignee: Crown Zellerbach Corp
Current assignee: Gaylord Container Corp; Fort James Corp
Priority date: 1967-11-28
Filing date: 1970-11-30
Publication date: 1974-02-05
Anticipated expiration: 1991-02-05

Abstract

EFFECTIVE AMOUNT OF DIMETHYL SULFOXIDE (DMSO), AS AN ESSENTIAL ACTIVE AGENT OR INGREDIENT, ARE ADMINISTERED TO ANIMALS TOPICALLY, BY INJECTION, BY INSTALLATION INTO BODY ORIFICES AND ORALLY FOR THE RELIEF OF SIGNS AND SYMPTOMS OF ANXIETY.

Description

United States Patent O 3,790,682 ATARATIC USE OF DIMETHYL SULFOXIDE Robert J. Herschler, Rte. 2, Box 1592, Camas, Wash., and Stanley W. Jacob, Oswego, reg.; said Jacob assignor to Crown Zellerbach Corporation, San Francisco, Calif.

No Drawing. Continuation-impart of application Ser. No. 686,295, Nov. 28, 1967, now Patent No. 3,549,770, dated Dec. 22, 1970, which is a continuation-in-part of applications Ser. Nos. 329,205, 329,208, 329,209, 329,- 238 and 329,271, all Dec. 9, 1963, Ser. No. 346,366, Feb. 10, 1964, and Ser. Nos. 417,781, 417,788 and 417,797, all Dec. 11, 1964, all now abandoned. This application Nov. 30, 1970, Ser. No. 93,841

Int. Cl. A61k 27/00 US. Cl. 424-337 3 Claims ABSTRACT OF THE DISCLOSURE Effective amounts of dimethyl sulfoxide (DMSO), as an essential active agent or ingredient, are administered to animals topically, by injection, by installation into body orifices and orally for the relief of signs and symptoms of anxiety. I

CROSS REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of our copending United States application Ser. No. 686,295, entitled Pharmaceutical Methods and Compositions with DMSO, filed Nov. 28, 1967, now U.S. Pat. No. 3,549,770, granted Dec. 22, 1970, which is, in turn, a continuation-in-part of applications Ser. Nos. 329,238, entitled Analgesia; 329,208, entitled Relief of Tissue Inflammation and Stimulation of Repair; 329,205, entitled Relief of Signs and Symptoms of Arthritis; 329,271, entitled Relief of Signs and Symptoms of Respiratory Distress; and 329,209, entitled Tranquilization, all filed Dec. 9, 1963; Ser. No. 346,366, entitled Control of Microorganisms, filed Feb. 10, 1964; and Ser. Nos. 417,781, entitled Muscle Relaxation; 417,788, entitled Treatment of Burns and Promotion of Skin Grafts and 417,- 797, entitled Relieving Symptoms of Vascular Insufficiency," all filed Dec. 11, 1964, all presently now abandoned, except for application Ser. No. 686,295.

BACKGROUND OF THE INVENTION This invention relates to the use of dimethyl sulfoxide as a pharmaceutical (i.e., as an essential active agent or ingredient) to treat signs and symptoms of anxiety, as will be discussed in detail herein.

For the various conditions treatable under the present invention, a considerable variety of medication and treatment exists. However, each has its limitations due to allergic response or potentially damaging side effects, restricted spectrum of activity (effective only in limited types of disorders), restricted routes of administration, lack of individual response in a certain percentage of individuals, expense, etc. Therefore, additional agents are constantly being sought which can replace, supplement or augment existing medication.

In achieving pharmaceutical effects, it is desirable to utilize an agent which is both well tolerated and conveniently administered. For its obvious advantages of patient acceptability and convenience, topical application is a particularly advantageous route. Relatively few pharmaceuticals may be efiectively applied topically to the skin and mucous membranes of the body cavities, particularly to obtain a response in disorders involving deeper tissues, structures and organs. Thus, with most pharmaceuticals the only alternative to esthetically undesirable injections has been through oral administration. Their usefulness has therefore been restricted.

Accordingly, it is desirable in the field of medicine to provide new pharmaceuticals which are favorably tolerated and are substantially nontoxic at effective levels of administration. It is further desirable to provide pharmaceuticals which may be administered conveniently and by a variety of routes, particularly topical.

The present invention has as a primary object to provide such a new, well-tolerated, substantially non-toxic pharmaceutical which is effective for treatment of emotional overactivity and depression and which may be administered by a variety of routes, including topical route.

Dimethyl sulfoxide (DMSO), originally synthesized in 1866, is a colorless liquid at room temperature which melts at about 18.5 C. and boils at about C. Over the last 25 years it has been used increasingly as an industrial solvent, reaction medium and chemical reactant and a considerable amount of literature has developed on its properties and industrial uses. It has been investigated for toxicity in experimental animals and for several biological functions, namely, as a protectant in freeze pres ervation of living tissue and as a radio protectant in experimental animals at high doses injected prior to radiation of the animals. Uses have also been discovered by one of the present inventors for dimethyl sulfoxide in the agricultural field, namely, the enhancing penetration of other agents into plants, in controlling plant virus and in stimulating plant metabolic functions.

Copending applications have also been filed by one of the applicants hereof concerning other discovered pharmaceutical properties of dimethyl sulfoxide and relating to enhancing animal tissue penetration of physiologically active agents with dimethyl sulfoxide. These include application Ser. No. 753,231, filed Aug. 16, 1968, and two contemporaneously filed applications entitled Enhancing Tissue Penetration of Physiologically Active Steroids with DMSO and Pharmaceutical compositions of DMSO with Physiologically Active Agents, respectively.

SUMMARY OF THE INVENTION Quite surprisingly, in the light of the long history, extensive experimentation, study and evaluation of this compound, it has now been discovered that dimethyl sulfoxide (DMSO) has previously unrecognized valuable and extensive pharmaceutical activity. In applicants copending parent application Ser. No. 686,295 is disclosed a number of such discovered activities, including activities as an antiinflammatory agent, analgesic muscle relaxant, tissue repair agent and agent for relieving vascular insufliciency. The present application is directed to another discovered activity, namely, the use of DMSO to treat signs and symptoms of anxiety. Dimethyl sulfoxide is rapidly rendered systemic in the body from all normal routes of administration and, importantly, also that it may be applied topically to the intact skin or mucous membrane to achieve highly unusual rapid absorption for systemic elfect.

GENERAL DESCRIPTION OF THE INVENTION The phenomenon of ataraxis or tranquilization is the relief of the higher neural centers of an organism from the disordering eifects of anxiety, such as tension, loss of emotional control and equilibrium, depression, anergy and like signs and symptoms. Anxiety may be the result of traumatic events, such as physical injury, pain, fear and frustration, and it is a common factor in most mental diseases, including neurotic and psychotic states. A recognized class of drugs has been developed, including the widely used chlorpromazine and the meprobamates for treating organisms suffering from the manifestations of anxiety. These drugs are characterized by reducing the overactivity or lessening emotional excesses and anxiety tensions and the like and by exerting an antidepressant effect on anergic individuals, particularly in neurotic and psychotic disorders. It is a characteristic of these drugs that they attain in desirable properties without unduly depressing the central nervous system or the consciousness or alertness of the subject. This class of drugs has frequently been referred to as tranquilizers, or ataraxics.

In addition to its well-known employment in human medication, including clinical and sub-clinical psychiatric and psychotherapeutic treatment, ataractic medication has become well established in veterinary and related medical practice. In common veterinary experience, animals of many kinds may become excited, with harmful results to themselves and their handlers by the occurrence of anxietyproducing events, such as medical procedures, handling, exposure to unfamiliar surroundings, etc. Ataractic agents are usefully employed in managing veterinary animals, for example, dogs, horses, cats, etc., under such circumstances.

Similarly, dimethyl sulfoxide has a tranquilizing or ataractic effect in the same sense of alleviating the signs and symptoms of anxiety. The particular amount of dimethyl sulfoxide to be administered to alleviate the manifestations of anxiety will understandably be determined by the expertise of the attending practitioner who considers the nature and severity of the manifestations, the response desired or observed, and the subject. A great degree of emotional overactivity or depression will normally urge the practitioner to administer higher concentrations of dimethyl sulfoxide in greater amounts, more repeatedly, say, an amount to obtain a daily dosage of 15 to 20 cc. of dimethyl sulfoxide. An effect, however, may often be obtained by only one or two treatments of only a few oc.s of dimethyl sulfoxide compositions containing anywhere from about 25% to 100% of the compound.

Dimethyl sulfoxide may be administered by the usual oral and injectable routes, and it may be applied topically to a cutaneous region or to the mucous membranes of the various body cavities as by direct application or instillation. This may be done by applying a small volume such as 2 to 5 cc. of a composition containing at least about 50% dimethyl sulfoxide and repeating the dosage as necessary.

Generally, as illustrated by the examples which follow, the dosage may be as low as 0.01 gram per kilogram body weight and the optimum amount anywhere from around 0.02 to 0.05 up to 1.0 gram per kilogram of body weight per day or somewhat higher in a few instances. The average individual dose may be in the neighborhood of 0.1 to 0.2 gram per kg. *body weight. However, the optimum dose will depend to a considerable extent upon the type and extent of the disorder and the mode of application.

The treatment may be repeated once or twice daily, or even more frequently, until appropriate response is obtained or for the duration of the complaint. For some indications (such as many acute situations), only one or two applications involving a few cc.s of dimethyl sulfoxide may be necessary, while in chronic situations a more sustained regimen for a prolonged period or follow-up treatments may be called for. In any case, the optimum amount for a given disorder will depend upon the factors previously mentioned.

Topical application to cutaneous regions such as the skin and mucous membranes will lead to absorption so the vascular system will carry the compound to the central nervous system where the tranquilizing effect will occur. It is a unique advantage that dimethyl sulfoxide penetrates or is absorbed in a surprising manner through the cutaneous regions. Although the topical route may be preferred, local injections may also be employed and preferably lower concentrations of 1% to 20% dimethyl sulfoxide are used for this purpose.

Topical application to a surface area rich in blood vessels (as, for example, on the chest, back, legs and arms) is quite convenient. Higher concentrations are preferred for topical applications, such as at least 25% and, more often, at least about 50%. The dimethyl sulfoxide composition may be applied by means of a cotton swab or other soft applicator. It may be conveniently applied in the form of a spray by means of an aerosol bomb or an atomizer or in a thickening base, etc. Desirably, at each application the surface treated is thoroughly wetted. Where large areas are to be treated, it may be desirable to immerse an entire limb, torso, or body into a dilute aqueous solution of dimethyl sulfoxide. At the lower concentrations greater volumes of dimethyl sulfoxide solutions may be administered more frequently as with bathing solutions for some purposes. Less frequent applications may be effectively made with solutions containing at least about 50% of dimethyl sulfoxide.

Composition and dosage forms include undiluted dimethly sulfoxide or, more preferably, dimethyl sulfoxide along with appropriate pharmaceutical diluents, excipients or adjuvants. In general, concentrations of dimethyl sulfoxide may vary from 1% to For topical use, however, higher concentrations of from 10% to 25% and above for application to mucous membranes and at least about 50% for dermal application are preferred. For more information on dosages, composition forms and routes of administration, reference is made to copending application Ser. No. 686,295, the disclosure of which is incorporated herein by reference.

The following example is illustrative:

Example The effective anti-anxiety activity of DMSO may be evidenced by the standard testing techniques which have been utilized for assessing such activity. One of the most prominent of such tests is that developed by Geller and Seifter utilizing a conflict situation or discriminated punishment schedule, as described in their articles Effects of Mono-Urethans, Diurethans and Barbiturates on Punishment Discrimination, J. Pharmacol. & Exper. Therap. 136:284, 1962; and Elfects of Chlordiazepoxide and Chlorpromazine on Punishment Discrimination," Psychopharmacologia 3:374, 1962.

A test model was set up as described in the latter mentioned article utilizing a Skinner box and associated programming equipment. A flashing light stimulus was utilized in place of an auditory stimulus.

Twelve male albino rats of Holtzman Sprague Dawley strain approximately eight weeks old at the start of the experiment were used. The rats were trained to press a lever in the Skinner box for a milk reward. When the lever-pressing rats had stabilized at an average of one reward every two minutes, a flashing light stimulus of three minutes duration was introduced at fifteen-minute intervals, together with a punishment contingency so that all lever responses during the light stimulus not only produced the liquid food reward but also an electric shock to the animals feet.

The animals were observed to respond infrequently during the conflict period, that is, they did not choose to press the lever for a food reward while subjected to the flashing light stimulus.

To each of six of the rats 1 gram per kg. of body weight of DMSO was then administered by intraperitoneal injection of an isotonic saline solution containing 25% by Weight of DMSO. Within one hour the DMSO-treated rats were seen to respond with twice the frequency of lever presses during the conflict periods, as compared to the control group of rats. This increased rate of response endured for four hours. The animals in both the test group and the control group maintained a steady rate of re spouse of an average of one reward every two minutes. The test was replicated by again administering DMSO in the same dosage to the test group of rats and the same results were observed.

The foregoing invention can now be practiced by those skilled in the art. Such skilled persons will know that the invention is not necessarily restricted to the particular embodiments presented herein. The scope of the invention is to be defined by the terms of the following claims, as given meaning by the preceding description.

We claim:

1. A method of relieving signs and symptoms of anxiety in a mammalian subject suflering therefrom which comprises administering to the mammal a nontoxic amount of dimethyl sulfoxide effective to relieve signs and symptoms of anxiety.

2. -A method as in claim 1 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1 gram per kg. of body weight per day.

3. A method as in claim 2 and wherein said dimethyl sulfoxide is administered to said subject topically to the intact skin in a composition containing at least 50% by weight of dimethyl sulfoxide.

References Cited UNITED STATES PATENTS 3,549,770 12/1970 Herschler et al. 424337 3,551,554 12/1970 Herschler 4247 OTHER REFERENCES Uramura (Igaku Kenkyu 2235-61 (1961), English translation, 16 pp. An Experimental Study on the Toxicity of Dimethyl Sulfoxide Used as a Solvent.

Brown et al., J. Pharm. & Pharmacol. 15: 688-692, October 1963, A Note on the Toxicity and Solvent Properties of Dimethyl Sulfoxide."

Ferm Lancet, I an. 22, 1966, pp. 208-209, Teratogenic Effect of Dimethyl Sulfoxide Ramirez et al. Ann. New York Acad. Sci. 141 Art 1.:655-667, Mar. 15, 1967, Dimethyl Sulfoxide in the Treatment of Mental Patients.

SHEP K. ROSE, Primary Examiner