Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 1 6~5~6
MEDICINE E~ECTIVE ~OR WARMBLOODED ANIMALS
COMPRI5ING, AS AN ESSENTIAL INGREDIENT,
A GERMANIUM-CONTAINING ORGANIC POL~MER
f
The present ~n~ntio~ relate~ ~o me~icines, in
particular, those effective for human hyperten~ion,
cardiovascular disturbances such as arrhythmia, angina
pectoris, myocardial infraction, encephalomalacia,
cerebral apoplexy, viral disease, tumor, cataract, chronic
respiratory disease, (usually referr~d to as C. R. D ) and
so called C. R. D. complex caused by mixed infection of
various pathogens.
In recent years, attention has been drawn to
germanium-containing organic compounds in view of their
pharmacological activities, which have been disclosed in
Japanese Patent Publication No 2964/74, Japanese Patent
Application Laid Open No. 61431/73, Japanese Patent
Publication Nos. 21855/71 and 2498/71, etc. The germanium-
containing organic compound disclosed in these publications
is a low molecular weight compound represented by the formula:
(GecH2cH2cooH)2o3 -
As a result of extensive investigations on the synthesis
of germanium-containing organic compounds other than the low mo]e-
cular weight compound represented by the formula:
(GecH2cH2cooH)2o3
1 1 B25~ 6
-- 2 --
with attention to the pharmacological activities of the
germanium-containing organic compound, the present inventors
have found novel germanium-containing organic polymers and
the process for the production thereof as well as their use as
medicines.
The present inventors have further found that the
novel germanium-containing organic polymers exhibit particularly
good pharmaceutical effects against hypertension, cardiovascular
diseases, various cancers, cataract, viral diseases and
mycoplasma diseases.
Specifically, the present germanium-containing
organic polymers have advantageous features in that they show
only a very low toxicity (acute toxicity: LD50 for rats by
oral administration is more than 10,000 mg/kg, which is the
maximum oral dose and, actually, no more amount can be applied
being restricted in view of the inside volume of rat's stomach),
they are both adaptible to rats of spontaneous hypertension
(SHR) (as disclosed herein) and to human hypertension, as
disclosed herein to reduce the blood pressure properly but not
below the normal level. Further, they are also effective for
the recovery from cardiovascular diseases such as arrhythmia,
myocardial infraction, encephalomalacia and cerebral a~oplexy.
mc(rkecl
Moreover, the present polymers have rcmar~cd
therapeutic effects against various viral diseases including
viral skin diseases (see Example 5 below).
~ 1 62S~6
-- 3 --
Furthermore, it has surprisingly been confirmed also
that the present germanium-containing organic polymers show
distinctive anti-tumor effects against various cancers (see
Example 3 below), therapeutic effects for human cataract
(see Example 4 below), as well as therapeutic effects for C. R.
D. or against so called C. R. D. complex by mixed infection of
other pathogens (see Example 6 below).
The germanium-containing organic polymers having the
foregoing effects are represented by the following formula (I)
or (II):
A B
( = GeCH - CH - CZ)nl Sn . (I)
or
OH A B
( - o - Ge - CH - CH - CZ)n (II)
wherein A is a hydrogen atom, an alkyl group having 1 to 3
carbon atoms, -COOH, -COOR (wherein R is an alkyl group
having 1 to 3 carbon atoms),
~ , ~O~ or
'~ ;
N
B is hydrogen atom or an alkyl group having 1 to 3 carbon
atoms;
Z is a hydroxy group, an alkoxy group having 1 to 3 carbon
1 3 62~6
atoms or an alkyl group having 1 to 3 carbon atoms;
n i~ an integer greater than 3, inclusive.
Of the germanium-containing organic polymers
represented by the formulae (I) and (II), particularly
preferred are those wherein A is a hydrogen ~rhr~b~ a
methyl group, -COOH,
~ ~ ~ ~ or
B is a hydrogen atom or a methyl group; and Z is a hydroxy
group, a methoxy group, an ethoxy group or a methyl group.
Representative examples for preparing the
germanium-containing organic polymers of the present
invention are illustratively shown below.
HX HX
GeO ~ GeX2 ~ HGeX ~ --~ H + GeX .................. ..(1)
2 H3PO2 3 3
or
M2HPO2 (M is a metal or ammonium ions)
HGeX3 ~ A B A B
~1 ~ + CH = C - COZ X3GeCH - CHCOZ............... (2)
H + GeX3
J (~) (II)
- 1 1 6~5~ 6
A
,0
X GeC~ Cl-IC07, . ~ low molecular weight polymer ....... (3)
3 organlc
solvent
1-120
low molecular weight polymer ttl ~ high molecular weight
polymer ...... (4)
In the reaction schemes (l), (2) and (3), A, B and
Z have the same meaninqs as defined above, X is a halogen
selected from chlorine, bromine and iodine, and the low
molecular weight polymer and the high molecular weight
polymer shown in the reaction schemes (3) and (4) are
germanium containing organic polymers represented by the
formulae (I) and (II) which are objective compounds of the
present invention. Whether the objective compound is of
high molecular weight polymer or of low molecular weight
polymer is determined by the number of n, more simply,
depending upon the solubility of the compound in water.
In the accompanying drawinqs:
Fig. 1 shows an infrared absorption spectrum for
one example of a polymer used in this invention;
Fig. 2 shows a powder X-ray spectrum of the ahove
polymer;
Fig. 3 shows the relations between the blood
pressure and the heart weight of spontaneous hypertension
rats and the administration of the medicine according to
this invention;
7 ~ ~7,546
-- 6 --
Fig. 4 shows the course of the reduction in the
blood pressure with time for hypertension patients by the
administration of the medicine according to this invention;
Fig. 5 i9 electrocardiographs on arrhythmia
patients before and after the administration of the medicine
according to this invention;
Fig. 6 is electrocardiographs on angina pectoris
patients before and after the administration of the medicine
according to this invention;
Fig. 7 shows the survival rate of rats by the
elapse of time for rat adcites liver cancer AH 66 strain with
the administration of the medicine according to this invention;
Fig. 8 is a sketch showing lungs of pulmonary
glandular cancer patients before and after the administration
of the medicine according to this invention; and
Fig. 9 is a sketch showing lungs of cutaneous-
liver cancer patients before and after the administration of
the medicine according to this invention.
It is apparent from the infrared absorption
spectrum (Figure 1), x-ray diffraction spectrum of powders
(Figure 2), and the like that the compounds in accordance with
the present invention are novel compounds different from
heretofore known compound: (GeCH2CH2C02H)203.
~ 1 6~5~ ,
- 7 -
The foregoing pharmacological effects of the
germanium-containing organic polymers according to this
invention are to be described specifically. The germanium-
containing organic polymers used for the purpose are prepared
by the synthetic processes described below and have such
properties as shown by the infrared absorption spectrum and
by the powder X-ray diffraction analysis in Fig. l and Fig. ~.
Preparatory Example
Preparation of a low molecular weight polymer (A) of 3-oxygermyl-
propionic acid:
In 1.3~ of acetone, a solvent miscible with water,
was dissolved 252 g (l mol) of 3-trichlorogermylpropionic
acid. To the solution, 1.3~ of water was added with stirring
White hairy crystals were precipitated out. The reaction
liquid was allowed to stand overnight. Then, crystals were
collected by suction-filtration The so obtained crystals
were washed with acetone sufficiently, followed by drying
under reduced pressure. White needle-like low molecular weight
polymer (A) was obtained in an amount of 144 g (85% in yield).
In addition, also in the case where other solvents which
are miscible with water (e.g., ethanol, methanol, cellosolve,
aceton~trile, tetrahydrofuran, dioxane, dimethoxyethane,
diglime, dimethylsulfoxide, dimethylformamide, etc.) are
employed in place of acetone, the low molecular weight
polymer (A) can also be obtained likewise at high yield.
~urthermore, the low molecular weight polymer (A) can also
be obtained using solvents which are immiscible with
water (e.g., chloroform, methylenechloride, carbon
~ 1 6~
-- 8 ~
tetrachloride, benæene, ether~ etc.). In this case~ the
low molecular weight polymer (A) was precipitated out when
a solution of 3-trichlorogermylpropionic acid was throughly
shaked with water. Crystals of this low molecular weight
polymer (A) neither decompose nor melt at temperature below
320 C. It is found that the polymer differs from the
germanium-containing organic compound prepared in accordance
with the method described in Japanese Patent Publication
No. 2964/71 since infrared absorption spectrum and X-ray
diffraction spectrum of powders are completely different.
In addition, the low molecular weight polymer (A) was
relatively easily soluble in water and the solubility in
water was about 1 g/100 ml (25 C).
Pharmacolo~ical Effects of the Germanium-Containin~ Compound A
This invention is to be described in more details
by way of the following Examples which illustrate the
pharmacological effects of the germanium-containing compound
A prepared in the Preparatory Example mentioned above.
Example 1: Effects on Rats with Spontaneous Hypertension
~ he compounds were orally given to rats with
spontaneous hypertension over 4 consecutive months at a
daily dosage of 100 mg/kg. Blood pressure was examined 7
months after. Then, the rats were sacrified to weigh the heart.
The results are shown below (see Table 1 and Fig. 3).
~ ~9 ~3 p) c9 ~
~ , o '1 ~ o ~ 1 1 6 2 5 ~ 6
~ ~ W ~ ~ O ~O ~ C ~ ~ n ~ W t~ t ~D
. ~ ~ o
~D ~ O
= = = = = = == = ,~ I
~D
= = =, =
~D
P~ o~ o
, ~, ~, , ~ ~ , , , ~ t~
' 3 ~D
00 ~ O W ~ W O
1'~
1~ ~ ~+
~O ~ ~ O O ~ ~ ~ ~ D ~ ~D
~ O C~ ~n O ~n O O W O O 0~ a~ o ~n ~
~3
r~
t' I' )~ y ~ ~ ~ ~D
o ~ ~o o~ ~ ~ ~~ o~ ~ o ~ ~ ~o o ~ ~
o a~
U)
I' 1- 1' 1' ~ 1' 1-- 1-1- 1' 1-- ~ 1' 1' 1- ~ ~t
~ O~ ~n ~ Oo ~ OC~ W ~D ~O ~ 3 (D
~ O ~ 0~ ~ ~\) 00CX) ~ I' a~ o ~ co \J~ ~
~D
I' 1- 1- ~ 1' 1' 1' 1-1- 1' 1' ~1' 1' 1-
~ ~ O~ ~ ~ ~ ~ W~ O 1~ O ~ 1- ~ tD
O~ O ~ ~ O ~D 1' 0 W~ ~
U
0
w~ ~ ~o ~D O 1~ ~ ~D 00 0 P.
0~ ~ 0~ W O C~ O ~ n ~
ID
N ~
. 0
1- 11 ~ ~ ~D
n ~O O ~O 1' ~ ~ ~ O ~ 11
CO O W C~ ~ t\) W ~ ~ 00 ~ ~ W 1~ `C
. ~D
WWW~WWWW ~WWWWWWW
W ~ W Go W W ~n ~~ ~ ~ n W ~J W ~D O 1'-
W 00 ~ ~o 1_ o o~ IJ0~ Co O ~ ~ ~ ~ ~ IJ.~, ~
aq ~ ,_
~ i- Y ~ I' ~ ~ ~ 1-
..... ,.......... ........ ~D
n ~ W O~ 00 co 00 ~ Go ~ 0~ ~ ~n ~
~ ~o co ~ w (O o~ ~ ~ ~ ~
a~ ~t
~ 1 B2~8
-- 10 --
It can be seen from the Table 2 and Fig, 3:
~1) No difference in blood pressure between the control
group and the medicated group was noted before the initiation
of the test,
(2) Blood pressure in the medicated group was obviously
lower than that of the control group after administration
for 126 days.
(3) Comparing heart weight at the 126th day, the heart
weight of the medicated group was clearly lighter than that
of the control group~
Example 2: Therapeutic Effects on Human Cardiovascular
Diseases
~ lood pressure reducing effect was observed for
hypertension at a daily dose of 10 mg - 90 mg/adult (50 kg
body weight) or more amount depending on the symptoms.
Fig, 4 shows specific examples. This example shows the course
of the improvement in the maximum blood pressure of a 52
years old man with hypertension by a daily dose of 40 mg/adult
(50 kg body weight) for consecutive 40 days,
Apparent improvements were also observed on
ECG findings for angina pectoris, cardiodisfunction and
arrhythmia by a daily dose of 10 mg - 90 mg/adult (50 kg
body weight) or more depending on the symptoms, Specific
findings are shown for arrhythmia in Fig, 5 and for angina
pectoris in Fig, 6, Fig. 5 shows ECG findings on a 60 years
old man patient with arrhythmia for the case (a) before
11 1 1 625~6
administration and for the case (b) after consecutive 10
day's administration at a daily dose of 30 mg/adult
(50 kg body weight). As can be seen from the figure,
distinctive improvement was attained in the arrhythmia.
Fig. 6 shows ST wave findings on a 63 years old woman
patient with angina pectoris for the case (a) before
administration and for the case (b) 15 minutes after the
administration at a daily dose of 40 mg/adult (50 kg body
weight), in which pulse normalization is shown
Furthermore, antihemorrhagic activity, promotion
for blood circulation~ improvements in neurocirculatory
osthenia and in plumonary edema were also observed after
one month at the shortest and after more than six months at
the longest by a daily dose of 10 mg - 90 mg/adult (50 kg
body weight) or by a more amount depending on the symptoms.
Example 3: Anti-Tumor Effect
(1) Therapeutic E~fects on Ehrlich Cancer
7.5 x 10 cells of Erhlich cancer were app]ied to each
of 10 mice through intravenous injection and, after 72 hours~
the germanium polymer was given orally for lO consecutive days.
at a daily dose of 100 mg/kg. The results are shown in
Table 2.
- lZ 1 1 625~ 6
Tabel 2
Experiment Dose Days of Number of
group (mg/kg/day survival survived mice
oral: 3 days at 40th day
after cancer (mice survi~ed/
cell innocula- total mice)
Control 0 21 22 23 24 25
(not-treated) 0/10
25 25 28 28 29
.. _ _ _ ,
Treated 21 22 25 28 31
with
germanium 100 36 survival
polymer (A)
of the survival 4/10
preparatory
Example survival
survival
As can be seen from the Table 2, the number of
surviving days was evidently prolonged and the number of
survived mice was also increased.
(2) Effects against Lewis Lung Cancer
1 x lO cells of Lewis lung cancer were inoculated
subcutaneously to each of a group of mice and, from the next day of the
inoculation, the germanium-containing organic polymer (A)
(obtained by the Preparatory Example) was given once per day
through oral administration for consecutive 5 days. The
decrease in the weight of the tumor was observed. The results
are shown in Table 3.
~ ~ fi2~
- 13 -
Table
~ . _ - - _
Administration Weight of solid Inhibi-
schedule tumor at 14th tion for
Experiment periods route dose per (average value tumor
grouponce g + standard (o~)
(day (mg/kg) deviation)
ControlI ~ 1 71 ~ 0.804
Ge-organic 1 - 5th oral 100 1.67 + 1.211 2,3
polymer from days
preparatory after 300 1.29 + 0.453 Z4.6
Example inocula-
tion of 500 1.40 + 0.517 18.1
cealnlSer _ ,
(3) Effects on Rats with Ascite~s Liver Cancer AH 66 Strain
107 cells of AH-66 strain of ascites liver cancer
were inoculated m travenously to each of a group of Donryu rats and,
from after the third day, the germanium~containing low molecular
weight organic polymer (A) prepared as in the Preparatory
Example was applied through oral adminis-tra-tion once per day
for consecutive 10 days at a dose of 100 mg/kg.
As the results, the survival days were prolonged
and the number of survived rats were increased as shown in
~ig. 7~
(4) Effects on Human Cancer
The germanium-containing organic polymers according
1 1 ~2546
-- 14
to this invention are effective against various human
cancers such as stomach cancer, lung cancer, uteru3
cancer and prostatic cancer, and their therapeutic effects
are shown here for pulmonary glandular cancer and skin cancer
metastasized from liver.
(A) Therapy for Pulmonary Glandular Cancer
The germanium-containing polymer was applied to a
71 years old woman patient with pulmonary glandular cancer
at the upper right pulmonary lobe for three months
consecutively at a daily dose of 30 mg. As shown in Fig. 3,
most of cancer focuses disappeared. In the figure, (a)
schematically represents the lung having the cancer
focus (c) before the administration and (b) schematically
represents the lung after three month's administration.
~B) Therapy for Liver Metastasized Cutaneous Cancer
The germanium-containing organic polymer was
applied to a 69 years old man patient with liver-metastasized
cutaneous cancer at the cervical region for two months at a
daily dose of 90 mg. The patient was almost completely
healed as shown :in Fig. 9. In the figure, (a) schematically
represents the liver having liver-metastasized cutaneous
cancer (c) before the administration and (b) schematically
represents the liver after the two months~ administration.
Example 4: Effects on Cataract
.. . . _ _ _ _
It has been found that the germanium-containing
organic polymers (A) according to this invention are also
1 ~ 6 2 ~ 4 ~
.
effective agai.nst cataract, which is considered as one of
most refractory ophthalmologic diseases.
An eye-lotion with pH at 7.2 was prepared by
dissolving the germanium-containing ~ow molecular weight
polymer as 1/~ strength into Politzer~s solution (containing
10 ml of 0.2% boric acid solution + 90 ml of 0~05% borax
solution, at pH 2.11). A cup f`illed with the eye-lotion
was contacted to the eye and an electric current was applied
by the Itoh~s ionophoresis. ~s one course of the ionophoretic
therapy, 1.0 - 1.2 mA of current was applied each time in
5 - 6 minutes for 10 times on every other day.and for
further lO times. Approximately the same effects w0re also
obtained by the consecutive oral admini.stration of the
germanium-containing low molecular weight organic polymers
at a daily dose of 10 - 150 mg/adult (50 kg body weight)
although it takes a longer tIme than that in the ionophoretic
therapy.
The results of the ionophoretic therapy are as
shown in Table 4.
S ~ fi
- 16 -
(A) Found much effective Treated patient ~ much effective (o/O)
1 initial cataract 3/3 100
2 immature cataract 8/11 (72)
_ _ '
(B) Found a little T t d ti t a litt e effective
effective (o/o)
.
1 immature cataract 3/11 (27)
2 mature cataract 5/5 (100)
3 capsular cataract 4/4 (100)
Example 5: Effects on Viral Diseases
(1) Effects on DNA Type Viral Disease
It was confirmed that the germanium-containing low
molecular weight organi.c polymer (A) obtained in the Preparatory
Example was markedly effective to viral cutaneous diseases.
The dose of the polymer is as below:
Infants: 10 mg (divided in twice on every day)
Children older than 7 years old: 20 mg (divided in twice on
every day)
Adults: 30 mg (divided in three times on every day)
Effects for various viral cutaneous diseases are
shown below in Tables 5, 6 and 7.
2~ 6
- 17 ~
Herpes Group Virus
. _ . I
PatientNumber of Consecutive period Number and percentage I
patient for therapy of patients showing
rapid administration
(day) ( / )
Water pox 8 2 - 5 7 (87.5)
Herpes11 2 - 7 ll (100 !
zoster _
1 J 62~4.6
- 18 ~
Table 6: Herpes Group Virus
Juvenile Verruca Planu~
. ~
Period from less than 1 - 3 3 ~ 5 more~than more than
onset to 1 year years years 5 years 10 years
therapy
total
Avera6e days
till the
polymer 5 days 34 days _ 90 days 90 days
found
effective
_ _ _ .. .__.
Average days
till complete 17 days 63 days _ 180 days ?
elimination
Tatseals 7 cases 1 2 3 ~ s ~ases
.
Hasaesed 5 cases 2 _ 2 _ 9
_
Effective 2 cases 2 _ _ 2 cases 6
cases (inter- (inter-
rupted) rupted) _ _
Although verruca became partially eliminated for 6
effective cases, complete healing cou]d not be observed since the
administration was interrupted.
1 1 6~6
-- 1 9 --
Table 7: Pox Group Virus
Infectious Molluscum Contagiosum
(1) Effects_on_Atopic Dermatitis
Period from onset to administration 1 month 2 months
Average administration day till
the polymer found effective 3 days 9 days Total
I
Total administration period 14 days 45 days
(average)
Total cases 3 4 7
~ _ _ .
Cases healed 3 3 6-
Cases effective
-
In effective cases partial elimination was shown
although the administration was interrupted after 21 days
In addition, the organic germanium compound of the
present invention is efficacious widely for DNA type virus
diseases of warm-blooded animals, for example infectious
bovine rhinotracheitis, feline rhinotracheitis, infectious
canine hepatitis, human molluscum contagiosum and condyloma
accuminatum and young men's plane wart.
- 20 - 13~25~6
(2) Effect9 on RNA Type Virus
The effects of the germanium-containing low molecular
organic polymer on mouse influenza, which is one of the RNA
type viral diseases were studied~
Virus of influenza A2/Adachi Strain was infected
through noses of d d.Y mice with 10 - 12 g body weight.
The amount of inoculation, oral administration of the
germanium-containing low molecular weight organic polymer
was started and it was consecutively given for 5 days at a
daily dose of 100 mg/kg and 300 mg/kg. 25 mice were used
for a group of experiments At 14th day~ they were anatomi~ed
for det~rrnining (1) rate of mortality, (2) visual pathogenic
changes in lung and (3) amount of the virus in the lung.
The pathogenic changes in the lung was estimated by scores
Specifically, 0 MeanS no pathogenic changes at all, 1 means
that pathogenic changes were observed in 1/4 region of the
lung, 2 means that pathogenic changes were observed in about
one-half region of the lung, 3 means that pat`hogenic changes
were observed in about 2/3 region of the lung and 4 means
that pathogenic changes were observed in the entire region of
the lung, in which each score was obtained by dividing the
to,tal number of the pathogenic changes in each of the mice
with 20. Estimation 4 was also allocated to such a case
where distinctive consol~ation was observed for a mouse~within
14 days. Contents of the virus in the lung were then
examined in the following procedures: Five out of twenty five
mice were sampled at random, homogenated and then inoculated
1 1 ~2546
- 21 -
on a petri-dish in which a single layer of fowl fibroblast
was formed. They were cultivated at 37 C for 3 days and,
thereafter, the resulted pathogenic changes were tinted
with neutral red, and the numbers were counted for the
contents of the virus.
The results of the experiment are shown below.
Experiment Dose Mortality Lung Virus content
group mg/kg/daY rate hypermia in lung
(%) (score) *reduction in
the content
Control 73.0 3.7 _
Germanium- lC0 60.0 1.9 90%
containing
~ow molecular 300 40 0 1.5 ggc/~
polymer .
* Reduction rate based on the virus content in the control group
as lO0.
It can be seen from the above results that the
germanium-containing low molecular weight polymer is also
effective against influenza diseases.
1 1 ~2~6
; 22 -
(3) Effect Against Sialodacrvoadenitis in Rats
Among coronaviruses that spontaneously infect
rats, one cau3es severe inflammation and necrosis of
salivary and Harderian glands. The enlargement of the
glands is transient and usually subsides in 3 to 7 days,
and the infection itself is not fatal and Dften occurs in
breeding stocks
The viral agent has an antigenic relationship
to mouse hepatitis virus (MHV) and, therefore, antibodies
reacting with MHV'in rat serum have been attributed to infection
by this coronavirus. The virus has been reported to be
extensively distributed in rat breeding colonies and in
wild rats. In infant rats, ocular symptoms are more
frequently prominent than enlargement of salivary glands~
and the infection tends to cause substantial damage to
laboratory animal production.
Four pregnant rats at comparable gestational
stage from a stock colony maintained in a quarter with a
widespread infection by the virus, where consistently
60 to 70% of animals had been found seropositive for
antibody to MHV with a morbidity rate (ocular) of about
20 to 30% over the past 2 years, were transferred to an
isolated animal room. They were divided into two groups,
of which one received -the'low molecular wei'ght polymer"(A)
in drinking water~ 0.5 g/l~000 ml~ ad lib. daily for a
period of 50 days beginning the 15th day of pregnancy. The
other group of 2 litters (10 sucklings) was maintained
1 :11 6 2 ~
: - 23 -
without medication~
After conclusion of the ~0-day treatment, all
rats were tested for serum antibody titer to MHV b~
the microtitration techniG of complement fixation
(Kolmer's modification). None of the rats in the treated
group was found po9itive and had ocular manifactations,
whereas in the untreated group, 7 animals demonstrated
significant serum antibody titers and 3 had symptoms of
the eye (Table 8).
Table 8: Serum titers of antibody+ to MHV
in untreated and the low molecular
weight polymer (A) treated rats
.... .
¦ Control group 20 - 10 20 40 10 10 - 40
Treated group - - ~ - ~ ~ ~ ~ ~ ~
+Reciprocal titer.
~ urthermore, the organic germanium compound of the
present invention is efficacious wide]y for the RNA type
virus diseases of warm blooded animals, for example,
parainfluenza, mumps, intestinal disturbances of warm
blooded animals due to the presence of rotavirus or corovirus
and so forth.
Example 6: Effects on C. R. D. or C0 R. D. Com~lex
No satisfactory methods have not yet been established
for surely healing C. R C. or C. R. D~ complex. The
1 ~ 6~6
- 24 -
present inventors have found that the germanium~containing
low molecular weight polymer is markedly effective against
the above diseases.
Inhibitorv Effect a~ainst Chromic Respiratorv Disease (CRD)
in Chickens, Pi~s, Rats and the like
l. Rats
Randomized ~0 male Wistar rats from the con-
sistently CRD-affected breeding colonies maintained at
this Laboratory were divided into three groups of 30 each and
transferred to an isolated, sterilized animal room. One
group received the low molecular weight polymer (A),
40 mg/kg/day, and another group tylosin tartrate, 20 mg/kg/day
in drinking water for a period of 10 days beginning 21
days of age immediately after weaning, the dosage of the
latter being such that would not be rejected by the rats
when administered in the manner described The third group
served as a control.
All rats in the three groups were sacrificed at
80 days of age and examined for CRD at autopsy. No
significant difference in morbidity was observed between
the tylosin-treated group and the control group whereas
there was practically no case of CRD in the low molecular
weight polymer (A) treated group (Table 9)
1 1 6~5~ 1
Table ~: Effect of the Polymer (A)
against CRD in rats
No~ of Rats No of Rats No. of Rats
Studied with CRD+ CRD
Control group 30 8 (++~: 6~ 1
( ++: 2)
Tylosin-treated
group 3 7 (+++: 6) 2
( ++: 1)
The polymer (A)
treated group 30 l ( +: 1) 0
+Gross pathologic pulmonary lesions: +++, lesions involving
more than one pulmonary lobe; ++, lesions limited within a
single lobe;
+, petechiae and/or a small lesion or lesions involving
only one lobe.
2. Swine Enzootic Pneumonia (SEP)
Two groups of 10 piglets, consisting o~ 5 each
from two farrows of lO each, were admitted to the clinical
trial at a sw:inery consistently infested with SEP All males
were castrated at 25 days of age. One group (8 males and
2 females) received the low molecular weight polymer (A),
300 mg/animal/day, in water daily ~or a period of 40 days
beginning at 30 days of age while the other group (6 males and
4 females) served as a control. At 120 days of age all shotes
were sacrificed and examined for CRD at necropsy, with the
- 26 ~ 1~6
re~ults indicating a marked suppression of CRD in the
low molecular weight polymer (A) treated group, compared
to the control group (Table 10).
Table 10: Effect of the low molecular weight
polymer (A) against swine enzootic
pneumonia
, I
No. of Piglets No, of Piglets No. of Piglets
Studied with CRD+ Succumbed
. . _ _
Control group 10 7 (++ 3) 0
( +: 4)
Polymer (A) 10 0 (+: 1) 0
_
Pulmonary lesions: ++, bilateral pl.euritis with pleural
adhesions, complicated by bronchiectasis; +, circumscribed
lesion of pneumonia invo]ving a single lobe; -, only an
îndex finger ti~-sized scar from healed pneumonia.
