US 2903396 A
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limited tates l atent THERAPEUTIC COR [POSITIONS AND METHOD FOR TREATING PARKINSONISM John Clarke Saunders, Orangeburg, N.Y., and Jack Lazarus, Jersey City, N.J., assignors to Ciba Pharma ceutical Products Inc., Summit, N.J., a corporation of New Jefsey N Drawing. Application May 8, 1957 Serial N0. 657,708
17 Claims. (Cl. 16765) This invention relates to compositions and methodsfor the treatment of paralysis agitans.
Paralysis agitans, commonly known as Parkinsons disease, is a degenerative process of that part of the brain known as the basal ganglia. The cause of the degeneration is unknown but the symptoms are readily detectable. Among the more apparent of these is a perculiar tremor and rigidity of either or both of the upper extremities. Although slow in onset, the tremors gradually become more and more noticeable, particularly when an attempt is made to write. As the disease progresses, the tremor and rigidity may become so profound that they completely incapacitate the afflicted individual.
Although Parkinsonism is, to date, an incurable disease, it is common practice to give at least symptomatic relief. This is usually done by means of drug therapy, surgery or a combination of both. Atropine, scopolamine, stramonium, trihexyphenidyl hydrochloride and similar palliatives have been used in the past but patients rapidly develop tolerances to these drugs and staggering of medications often becomes necessary. Since the disease is chronic, a point is eventually reached where drug administration becomes completely ineifective; Procaine injections are sometimes successful, but they too are temporary.
Attempts to obtain symptomatic relief from tremor and rigidity surgically have included removal of the basal ganglia, section of the pyramidal tract in the spinal cord and similar techniques. Tying off the anterior choroidal artery, which supplies blood to the globuspallidus and related pyramidal nuclei has also been attempted but it has proven to be dangerous since it causes loss or disease of the ganglion cells of the basal ganglia. Another disadvantage of this technique is the variability of the origin and distribution of the anterior choroidal artery, making it difficult for the neurosurgeon to coagulate and destroy it.
From a surgical point of view the target area for the relief of symptoms of Parkinsonism appears to be the globus pallidus, which is a small portion of the basal ganglia and which, when diseased, is contributory to the development of Parkinsonian tremor and rigidity. The destruction of this neurological center, if effected properly without acc mpanying obliteration of immediately adjacent vital areas, has been thought of as the best means for affording symptomatic relief. One of the methods heretofore employed for this purpose has been to inject a quantity of dehydrated alcohol directly into the globus pallidus preceded by an injection of procaine to confirm the location of the needle in the desired position. One of the more apparent disadvantages of this technique is that the alcohol frequently spreads to other vital areas, thus not only precluding the formation of a discrete lesion, but frequently causing extremely serious results such as hemiplegia or death.
We have now found that a composition comprising a mixture of ethyl alcohol and an alcohol-soluble thickening agent is useful for chemosurgical removal of Parkinsonian symptoms. The novel composition completely overcomes the disadvantages'of dehydrated alcohol per se. When injected properly into the globus .pallidus it becomes localized in this area resulting in the formation of a permanent, discrete lesion, which abolishes Parkinsonian tremors and rigidity without'loss of'motorpowers'. It will be noted that the addition of an alcohol-soluble thickening agent to ethyl alcohol not only localizes the effect of the alcohol after injection, thus insuring proper concentration in the globus pallidus, but also prevents the dissemination of the alcohol into the internal capsule, thus precluding fatal results.
A wide variety of alcohol-soluble thickening agents may be used in accordance with this invention, the only precaution being that the thickcners must be non-toxic and suitable for parenteral administration. Among those which we have found desirable for this purpose are various' celluloses such as ethyl cellulose, cellulose acetate phthalate, etc.; the higher fatty alcohols such as cetyl alcohol, stearyl alcohol; palmityl alcohol, and their corresponding acids; alcohol-soluble silicone resins, synthetic resins, gums, etc. Castor oil, which is one of the few fixed alcohol-soluble oils, can also be used. We prefer to use ethyl cellulose.
The amount of alcohol-soluble thickening agent to be combined with the ethyl alcohol is critical not only from the physiological point of-view, i.e. compatibility with tissue, but also because ofthe practical problems involved. Since an 18-gauge needle is usually employed for administration, the viscosity of the composition must be such as to permit easy flow through the bore of a needle of such diameter. Thus, if too much thickening agent is added to the alcohol, the mixture will not pass through the needle. If, on the other hand, an inadequate amount is added to the alcohol, the spread of the alcohol will not be impeded and attendant serious results may occur. We have found that a solution containing from about 0.5% to about 50% of thickening agent is suitable, the exact amount used depending largely upon the kind of thickener being employed. For example, if ethyl cellulose is used, a preferred range is from about 5% to about 20%. Optimally, we have found that'a concentration of from about 8% to about 10% ethyl cellulose affords the most desirable results. If cetyl alcohol is used as the thickening agent, it may be added in an amount varying from about 20% to about 40%. A preferred range is from about 25% to about 35%.
It is to be noted that although we have'described the applicability of the compositions of this invention to Parkinsonism, this is not to be construed as an intent to limit their use for this specific purpose. On the contrary, the compositions may be used for the relief of symptoms in a wide variety of hyperkinetic diseases such as psychomotor equivalents, Huntingtons chorea, athetosis, cerebral palsy, etc. and it is intended that the use or uses in the treatment of these diseases be included within the scope of'this invention.
The exact dose ofthe composition to be administered will vary somewhat from patient to patient depending upon the condition of the patient, the extent of the disease being treated and the desires of the administering surgeon. In general, a dose within the range of 0.4 ml. to 1.0 ml. may be administered directly into the globus pallidus. In practice it has been found that an. initial dose of about 0.4 ml. followed by a second dose within the above range about three days postoperatively is adequate for removing symptoms of Parkinsonian tremor and rigidity.
If desired, a small quantity of X-ray contrast material, for example an alcohol-soluble, iodinated, organic radiopaque substance suitable for parenteral administration, may be added to the composition for the purpose of enabling the surgeon to determine not only the exact location, but also the extent of the discrete lesion. An amount varying from about 1% to about 20%, preferably is adequate for this purpose. A wide variety of substances may be used, representative examples of which are the following: 3-acetamido-2,4,6-triiodobenzoic acid; ethyl iodophenylundecylate; ethyl ester of the iodinated mixture of oleic and linoleic acids of poppy seed oil (available under the trademark Ethiodol); ethyl diiodobrassidate; N,Nadipyl-bis-(3-amino-2,4,6-triiodo) benzoic acid; 3,5-diiodo-4-pyridone-N-acetic acid; fi-(3-amino- 2,4,6-triiodophenyl)-a-ethylpropionic acid; and l-methyl- 3,5-diiodo-4-pyridone 2,6-dicarbocyelic acid.
The method of preparation of the compositions is not critical. It involves admixing the desired quantities of alcohol and thickening agent thoroughly to insure complete solution (with heat if necessary) and sterilizing the resulting mixture at the proper temperature and pressure.
This is a continuation-in-part of our copending application Serial No. 587,225, filed May 25, 1956, and now abandoned.
The following examples are intended to illustrate the invention, but not to limit its scope:
Example 1 Ethyl cellulose, 20 cps. viscosity 8.0 Ethyl alcohol, 95% qs 100.0
Example 2 Cetyl alcohol 30.0 Ethyl alcohol, 95% qs 100.0
For preparation, follow directions given in Example 1.
Example 3 Ethyl cellulose, 20 cps. viscosity 10.0 Ethyl iodophenylundecylate 10.0
Ethyl alcohol, 95% qs 100.0
Dissolve the ethyl cellulose and the ethyl iodophenylundecylate in 85 ml. ethyl alcohol and mix until dissolved. Add suflicient quantity ethyl alcohol to bring the volume to 100 ml. Filter and sterilize under 10 lbs. steam pressure at 115 C. for 30 minutes.
What is claimed is:
. 1. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5% to about 50% of an alcohol-thickening agent and a radiopaque substance.
2. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5% to about 50% of an alcohol thickening agent and from about 1% to about 20% of a radiopaque substance.
3. A therapeutic composition comprising essentially a mixture of ethyl alcohol and from about 0.5% to about 50% cetyl alcohol.
4. A therapeutic composition comprising essentially a mixture of ethyl alcohol and from about 0.5% to about 50% stearyl alcohol.
5. A therapeutic composition comprising essentially a mixture of ethyl alcohol and from about 0.5% to about 50% stearic acid.
6. A therapeutic composition comprising essentially a mixture of ethyl alcohol and from about 0.5 to about 50% cellulose acetate phthalate.
7. A therapeutic composition comprising essentially a mixture of ethyl alcohol and from about 5% to about 20% ethyl cellulose.
8. A therapeutic composition comprising essentially a mixture of ethyl alcohol and irom about 8% to about 10% ethyl cellulose.
9. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5% to about 50% of an alcohol-thickening agent and from about 1% to about 20% ethyl iodophenylundecylate.
10. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5% to about 50% ethyl cellulose and from about 1% to about 20% ethyl idophenylundecylate.
11. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5 to about 50% of an alcohol-thickening agent and from about 1% to about 20% ethyl diiodobrassidate.
12. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5 to about 50% of an alcohol-thickening agent and from about 1% to about 20% of the ethyl ester iodinated mixture of oleic and linoleic acids of poppy seed oil.
13. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5% to about 50% of an alcohol-thickening agent and from about 1% to about 20% N,N-adipyl-bis-(3-amino-2,4,6-triiodo) benzoic acid.
14. A therapeutic composition comprising a mixture of ethyl alcohol, from about 0.5 to about 50% of an alcohol-thickening agent and from about 1% to about 20% 3,5-diiodo-4-pyridone-N-acetic acid.
15. A method for the treatment of Parkinsonism which comprises injecting a mixture of ethyl alcohol and an alcohol-thickening agent into the globus pallidus.
16. A method for the treatment of hyperkinetic dis cases which comprises injecting into the body a mixture of ethyl alcohol, an alcohol-thickening agent and a radiopaque substance.
17. A method for the treatment of Parkinsonism which comprise injecting a mixture of ethyl alcohol, an alcoholthickening agent and a radiopaque substance into the globus pallidus.
References Cited in the file of this patent UNITED STATES PATENTS 2,155,658 Hermann et al. Apr. 25, 1939 2,196,768 Hiatt Apr. 9, 1940 2,572,828 Archer Oct. 30, 1951 2,698,807 Asaii Jan. 4, 1955 2,704,270 Olsson Mar. 15, 1955 OTHER REFERENCES