Treatment of arthritis

Arthritis is treated by administration of azaspirane compounds, either germanium or silicon azaspirane compounds, preferably spirogermanium, most preferably dimethyl, diethyl, dipropyl or dibutyl. The diethyl or dibutyl are the most preferred.

BACKGROUND OF THE INVENTION 
Aside from the treatment of the pain associated with arthritis, with pain 
relievers such as aspirin and the like, the most beneficial results 
obtained in the management of arthritis is with the use of cortisone. 
Cortisone has, however, many limitations in its use, and there is 
considerable research for other drugs to be used in the management of 
arthritis. 
U.S. Pat. No. 3,825,546 discloses a series of azaspiranes containing 
silicon or germanium in a ring, in connection with the treatment of 
cancer. 
SUMMARY OF THE INVENTION 
Generally speaking, in accordance with the present invention, it has been 
discovered that certain specific compounds of U.S. Pat. No. 3,825,546, 
namely those which contain germanium in the ring, that is the 
spirogermaniums, particularly the dimethyl, diethyl, dipropyl and dibutyl 
spirogermaniums, including their acid addition salts and bis-quaternary 
salts, can be used in the treatment of arthritis. 
It is accordingly a primary object of the present invention to provide for 
methods of treating arthritis. 
It is a further object of the present invention to provide for the 
treatment of arthritis by the administration of an arthritis treatment 
effective amount of a spirogermanium. 
Other objects and advantages of the present invention will be apparent from 
a further reading of the specification and of the appended claims. 
The compounds of U.S. Pat. No. 3,825,546 which can be used for the purposes 
of the present invention are those compounds of the following structural 
formula: 
##STR1## 
wherein R.sup.1 and R.sup.2 are the same or different alkyl groups of 1-4 
carbon atoms 
x=germanium 
A and A.sup.1 are the same and either 
##STR2## 
n=0 or 1 B=CH.sub.2 when n is one and B is the same as A when n is zero 
R.sup.3 =alkylene or alkenylene 
y=2-6 when R.sup.3 is alkylene and 3-4 when R.sup.3 is alkenylene 
R.sup.4 and R.sup.5 are the same or different lower alkyls having 1-4 
carbon atoms, lower alkenyls having 3-4 carbon atoms, or cyclicized 
together form a heterocyclic group selected from morpholino, pyrrolidino, 
piperidino and lower alkyl (1-4 carbon atoms) piperazino in which said 
lower alkyl is attached to a terminal nitrogen atom, as well as acid 
addition salts and bis-quarternary salts thereof. 
The acid addition salts are of course the physiologically compatible acid 
addition salts, most preferably the dihydrochloride. 
The bis-quaternary salts are of course the physiologically compatible 
bis-quaternary salts including the methiodide and the dimethiodide. 
The dimethyl spirogermanium, diethyl spirogermanium, dipropyl 
spirogermanium and dibutyl spirogermanium which are effective in the 
treatment of arthritis are: 
N-(3-dimethylaminopropyl)-2-aza-8,8-dimethyl-8-germaspiro[4:5] decane; 
N-(3-dimethylaminopropyl)-2-aza-8,8-diethyl-8-germaspiro[4:5] decane; 
N-(3-dimethylaminopropyl)-2-aza-8,8-dipropyl-8-germaspiro[4:5] decane; and 
N-(3-dimethylaminopropyl)-2-aza-8,8-dibutyl-8-germaspiro[b 4:5] decane. 
As indicated previously, the above compounds may be utilized in the form of 
their acid addition salts or bis-quaternary salts. Most preferred are the 
dihydrochloride salts. 
The above compounds may be distributed in any suitable pharmaceutical 
carrier for administration by injection or for oral administration. 
Aqueous solutions can be prepared of the non-toxic salts which are soluble 
in water for administration by injection, for example intravenous 
administration or intraperitoneal injection, or for oral administration. 
It is preferred, however, for oral administration to utilize compositions 
in tablet form, for example tablets with lactose or the like as a carrier. 
Although the spirogermaniums can be tolerated in rather high doses without 
any adverse effects, it having been found safe when given intravenously in 
doses of 50-80 mg/m.sup.2 of body surface, and even doses of 120 
mg/m.sup.2 of body surface, much smaller doses can be administered for the 
purposes of the present invention. 
The recommended dose of spirogermanium therapy for the treatment of 
arthritis with severe rheumatoid symptoms is 1.5 cc intramuscularly of an 
aqueous solution of 30 mg/ml (45 mg/dose). Such treatment is given twice 
weekly for the first six weeks and once weekly thereafter until remission 
is obtained. This usually requires 3-6 months of treatment. 
Oral treatment can be effected by means of capsules containing 200 mg per 
capsule, beginning with two capsules daily for two weeks and one capsule 
daily thereafter for six weeks. 
For bouts of severe pain and disability, an intravenous drip of 10 cc 
spirogermanium (10 mg/ml) diluted in 100 cc distilled water may be 
administered over a period of one to two hours. 
Initial testing of the compositions of the present invention for the 
treatment of arthritis was effected by administration thereof to cancer 
patients with a chronic history of arthritis unrelieved by other methods 
of treatment. The major indication for the therapy for this initial 
testing was the presence of malignant disease in these individuals. In 
tests which will be described below, two of the patients had carcinoma of 
the breast, either with recurrence or metastasis and one had carcinoma of 
the lung that was inoperable. Beneficial results were achieved, and the 
clinical history of patients are summarized below.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following examples are given to further illustrate the present 
invention. The scope of the invention is not, however, meant to be limited 
to the specific details of the examples. 
EXAMPLE I 
A composition for injection was prepared of diethylspirogermanium dissolved 
in saline. The solution contained 100 mg spirogermanium per each 10 ml 
saline. 
EXAMPLE II 
A composition for injection was prepared of diethylspirogermanium dissolved 
in water. The solution contained 200 mg spirogermanium per each 10 ml of 
solution. 
EXAMPLE III 
All compositions were prepared by forming tablets of diethylspirogermanium 
and beta lactose with concentrations of 200 mg diethylspirogermanium per 
tablet. Capsules of the same composition were prepared. 
The following is a description of clinical case histories of arthritic 
patients treated in accordance with the present invention. 
A patient (F. G.) was first seen for arthritis at the age of 37. Salicylate 
therapy was only moderately successful and the patient received injections 
of ACTHAR Gel for bouts of severe pain during several intervals. The 
patient developed a cyst of the right breast, which was treated by 
aspiration and later a small breast nodule appeared in the left breast, 
which was excised and proved to be cancer. Radical breast surgery was 
refused by the patient. Post-operation irradiation was administered. Her 
arthritic symptons varied in intensity from time to time. The patient 
received alternate injections of silicone and germanium azaspiranes for 2 
months followed by injections of germanium azaspirane, namely 
diethylspirogermanium, (20 mg/ml) injected intramuscularly (in aqueous 
solution) twice weekly for 5 months. 
In the next 60 days, because of the presence of a recurrence of her mammary 
tumor, injections of germanium azaspirane (25 mg/ml intramuscularly) were 
given three times weekly for one month followed by injections twice 
weekly. The patient remained free of all arthritic symptons as well as 
absence of clinical evidence of her malignant disease for over one year. 
A 75 year old white female (I. G.) had mammary cancer treated by simple 
mastectomy with a recurrent mass appearing in the scar about 2 years later 
and lymph node involvement in the axilla after an additional 12 months. 
Metastatic cancer occurred in the skin and in the bone with a pathologic 
fracure of the right femur several years later. 
Arthritic pains with disabling symptons had complicated the long history of 
her illness and the patient was bedridden when injections of 
spirogermanium were started 3 times weekly at a dose of 45 mg/dose. 
Spirogermanium injections were continued with steady improvement of 
mobility and relief of pain for about 15 months. The patient later died 
suddenly of myocardial infarction. 
A married woman (M. G.) aged 65 had increasing osteoarthritis of the lumbar 
spine and both knees for a period of 6 years. In the last several years, 
rheumatoid arthritis affected the hands, knees and elbows. She had been 
able to pursue her hobbies of knitting and oil painting until the last 3 
years. Following a period of cough, pain in the left arm, and night sweats 
for 3 weeks duration, roentgenograms revealed a carcinoma of the left 
lung. This was confirmed by thorocotomy. 
Spirogermanium therapy was started. Injections were given 3 times weekly in 
doses of 45 to 60 mg/ml intramuscularly. All arthritic symptoms subsided 
after the first week of injections. This treatment was continued for 6 
months. A total of 2.2 grams of this compound had been administered during 
this period of approximately 6 months. 
While the invention has been described in particular with respect to 
specific treatments of arthritic conditions, it is apparent that 
variations and modifications of the invention can be made without parting 
from the spirit or scope thereof.