CA2027665C - Agent for preventing and treating opacity of lens - Google Patents

Agent for preventing and treating opacity of lens Download PDF

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Publication number
CA2027665C
CA2027665C CA 2027665 CA2027665A CA2027665C CA 2027665 C CA2027665 C CA 2027665C CA 2027665 CA2027665 CA 2027665 CA 2027665 A CA2027665 A CA 2027665A CA 2027665 C CA2027665 C CA 2027665C
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Prior art keywords
group
agent
preventing
opacity
treating
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CA 2027665
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French (fr)
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CA2027665A1 (en
Inventor
Susumu Sato
Norihiro Kakimoto
Mikio Miyata
Shigezo Uga
Kunie Nakamura
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Asai Germanium Research Institute Co Ltd
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Asai Germanium Research Institute Co Ltd
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention is to provide a highly effective agent for preventing and treating opacity of lens, contain-ing an organic germanium compound represented by the for-mula (1);
(see formula I) [wherein R1 to R3 represent hydrogen atoms, lower alkyl groups each of which may be the same or different and se-lected from the group consisting of methyl group, ethyl group, etc., or phenyl groups substituted or unsubstituted;
X represents a hydroxyl group, an O-lower alkyl group, an amino group or O-Y+ (Y represents a metal such as sodium, potassium, etc., or a compound having a basic group such as lysozyme and basic amino acid. etc.}] and a phenoxazine derivative.

Description

~0~'~~~~

AGENT FOR PREVENTING AND TREATING OPACITY OF LENS
BACItGROUND OF THE INVENTION
(FIELD OF THE INVENTION]
The present invention relates to an agent for prevent-ing and treating opacity of lens, more specifically, the present invention relates to a highly effective agent f.dr preventing and treating opacity of lens, the agent compris-ing a combination of specific organic germanium compound and phenoxazine derivatives.
[PRIOR ART]
Lens of eyes is composed of as principle components about 65% of water and about 350 of protein, the ratio of protein contained in lens being higher than other tissues do. Under a variety of bialogical controls, the protein in a high concentration, along with water inside cells, forms, and maintains lens in hydrophilic colloidal state to retain transparency thereof. If lens which should be transparent happens to get opaque by some etiology, however, the quan-tity of light to reach retina decreases. Thus, visual acu-ity through the lens generally deteriorates, depending on the degree of opacity induced.
As the etiology of the incidence of opacity in lens is diversified, it is quite difficult to discuss generally.
One of the proposed mechanism is such that the water-solu-ble, the membrane and the water-insoluble lens proteins de-scribed above, contain vast amounts of the SH group (thiol group), which are transformed into a S-S bond through bio-logical oxidative reaction, to form insoluble aggregated products, leading to the opacification of lens. The another most reliable explanation is that the aforementioned pro-teins react with sugars non-enzymatically and irreversibly to form reaction mixture called Amadori-products, of which reactions are general reactions between amino groups of proteins and carbonyl groups of sugars, known as Mailard Reaction. And this Mailard Reaction is considered to be key reaction leading to aging. Such explanation is considered to be one of the etiology for opaque lens. , The typical example of the disease associated with opaque lens is known as cataract, which is classified into congenital cataract and acquired one. The latter is further classified into senile cataract, trawnatic cataract and di-abetic cataract and others. In any type of cataracts, the formation of Amadori-products is cansidered to be a cause of opaque.
PROBLEMS THAT THE INVENTION IS TO SOLVE
One thing which is definitely clear in this field is that there has not yet been established any therapeutic treatment to prevent opacity of lens or reduce the opacity if it might happen.
That is, many problems have not yet been solved re-garding opacification of lens, including cataract as ex-plained above, so that specific agents for preventing or treating opacity of lens have not been developed. Thus, the 2~~'~~~

agents for exerting significant effects only on recovering visual acuity or blocking the progress of opacification are now currently used.
SUi~IARY OF THE INVENTTON
An object of the present invention is to provide an agent capable of efficiently preventing and treating opacity of lens.
Another object: of the present invention is to pro-vide an agent without toxicity or side effects, because such agents should be administered for a long period.
In order to achieve the above objects, the present invention is constructed to provide an agent for preventing and treating opacity of lens, the agent containing as the effective component the organic germanium campound repre-rented by the formula;
R1 Rs (Ge - C - CH - COX )2O3 (1 ) L
[wherein Ri to R3 represent hydrogen atoms, lower alkyl groups each of which may be the same or different and selected from the group consisting o~ methyl group, ethyl group, etc., or phenyl groups substituted or unsubstituted;
X represents a hydroxyl group, an O-lowsr alkyl group, an amino group or O Y+ [Y represents a metal such as sodium, potassium, etc., or a compound having a basic group such as lysozyme and basic amino acid, etc.}] and phenoxazine derivatives.
BRIEF DESCRIPTION OF DRAWINGS
FIGs. 1 through 6 show the percentage distribution of lens symptoms in each eye drop group.
FIGS. 1 through 3 show the results of administration of the eye drop containing the present agent to the mice aged 1 month and thereafter.
FIGS. 4 through 6 show the results of administration of the eye drop containing the present agent to the animals aged 5 months and thereafter.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be explained in detail hereinafter. The term "agent" employed in this specification should be understood to mean "pharmaceutical composition".
The agent for preventing and treating opacity of lens contains as the effective component the specific organic germanium compound represented by the formula (1);

(GeCCH-COX) z03 RZ
Explanation about the compound will be made firstly.
The principle structure of the compound is composed of germylpropionic acid where germanium atom is bonded to a propionic acid derivative having three substituents R1 to R3 and a functional group containing oxygen, i.e. OX, and the germanium atoms of the principle structure and the oxygen atoms are bonded in the ratio of 2:3.
Each of the substituents Ri to R3 herein represents a hydrogen atom, a so-called lower alkyl group such as methyl group, ethyl group, propyl group, butyl group, etc., or a phenyl group substituted or unsubstituted; the substituent X represents a hydroxyl group, an O-lower alkyl group, an amino group or O Y~ representing the salt of carboxylic acid, individually. Eubstituent Y represents a metal such as sodium, potassium or the like (the metal is not neces-sarily monovalent), or a basic compound represented by ba-sic amino acid and the like, such as lysozyme or lysine.
The substituents Ri and Rz, and the substituent Rs are bonded to the germanium atom at a and ~ positions, re-spectively. Thus, examples of organic germanium the the compound to be used accordance the present in with inven-tion are illustrated follows;
as ( Ge - CHa- CHz - COOH )zOs ( 1- 1 ) ( Ge - CH - CHz COOH )2O3 ( 1- 2 ) -CHs I
(Ge - CHz- CH COOH )2O3 (1- 3 ) -( Ge - CH - CH COOH ) 2O3 ~ ( 1 - 4 ) I -I
( Ge - C CHz COOH )2O3 ( 1 - 5 ) - -~0'~~
(Ge - CH - CHa - COOH )a0~ ( 1- 6 ) ( Ge - CH - CH - COOH ) 2O3 , ( 1- 7 ) CsHs ( Ge - CHa - CHa - COOCH~ ) a 03 ( 1- 8 ) ( Ge - CHa - CHa - CONHa ) aO3 ( 1- 9 ) ( Ge - CHa - CHa - COO Na+ )a03 ( 1-10 ) The organic germanium compounds having the above structure may be produced in various processes.
For examples, the compound wherein X is OH in the for-mula (1) may be produced as shown in the following reaction formula;
Reaction formula Ri Rs Ri Rs ClsGe - C - CH - COOH ~ (Ge - C - CH - COOH)aOs R2 (2) RZ
That is, trihalogermylpropionic acid in which the sub-s~ituents- Ri to Rs are preliminary introduced,, such as trichlorogermylpropionic acid (2) and the like, may be hy-drolyzed.
On the other hand, the compound wherein X is O-lower alkyl group may be obtained, for example, by reacting thionyl chloride, etc. with the above compound (2) to transform the compound into the corresponding acid halide and subsequently reacting alcohol corresponding to the above 0-lower alkyl group, followed by hydrolysis of the resulting compound. And the compound of the formula (1) ~~~'~~~
7?057-1~I
'wherein X is NH2 may be obtained, for example, by reacting ammonia to the above acid halide, followed by the hydrolysis.
The compound of the formula (1) containing COO-Y+
group as substituent X, wherein Y is a metal may be obtained, for example, by reacting metal hydroxide with the above compound (1), while the compound containing a basic group as Y may be subjected to known acid-base reaction.
The organic germanium compounds obtained in the above manner are subjected to instrumental analysis for nuclear magnetic LO resonance (NMR) and infrared absorption (IR) spectra, and the results strongly support that the above compound can be represented by the above formula (1).
The above formulas represent the organic germanium compounds in crystalline state, which are hydrolyzed in aqueous solution at germanium-oxygen bonding. For example, the above compound (1-1) transforms its original structure into the following structure;
OH
HO - Ge - CHI - CH2 - COOH
OH
Among the above compounds, the compound (1-1) may be preferable because of its easy availability.' The phenoxazine derivative to be used in accordance with the present invention is represented by the following prin-ciple structural formula and may have one or more substituents such as a lower alkyl group, a lower alkoxy group, a hydroxyl group, a carboxyl group and a lower alkoxycarbonyl group:
_ 7 _ N
Nw. \
\ \\
~O V O
and more specifically, 1-hydroxy-5-oxo-5H-pyrido(3,2-a)phenoxazine-3-carboxylic acid (general name; pyrenoxine) of the following formula;
HO / ~ COOH
N
Na \
''~ . \ ~~
or its salt with. metal such as sodium, potassium and the like may be preferable.
i This compound has been conventionally used for treat-ment of cataract. The outcome of such treatment has been reported in academic papers (For example, see Japanese Clinical Ophthalmology 11:272, 1957).
The other phenoxazine derivatives represented by the above principle structural formula are publicly disclosed in Japanese Patent Publication No.10570/1980.
The agent for preventing and treating opacity of lens in accordance with the present invention contains as the effective component the organic germanium compound synthe-sized in the above manner with the phenoxazine derivative described above; they rnay be prepared into eye drop, preferably, together with known components such as boric acid, sodium chloride, sodium hydroxide, or benzalkonium chloride, E-aminocaproic acid, methyl p-oxyaminobenzoic acid, and chlorobutanol, in addition to water.
The solubility of the organic germanium compound and the like as the effective components of the present invention may increase in a basic eye drop.
Since the organic germanium compound as the effective component of the present invention has characteristic features such as extremely low toxicity and little side effects, the amount thereof to be used in eye drop may be determined in relatively free manner. And phenoxazine derivatives have been used for treatment of cataract over a long period and therefore, the safety thereof has been evaluated and verified.
For example, the eye drop containing as the principle agents the organic germanium compound and the phenoxazine derivative may be prepared so that 5-500 mg of the organogermanium compound and 0.005-0.5 mg of the phenoxazine derivative may be contained in 1 ml of the eyed drop.
Furthermore, the agent containing the organic germanium compound and the agent containing a phenoxazine derivative may be separately prepared into formulations in advance, and then they may be mixed to prepare the agent of the present invention as needed basis.
ADVANTAGES OF THE INVENTION
The testing of the effects of the agent of the present invention in senile accelerated mice susceptible to opacity of lens, indicates such effects as the decrease in number of opaque eyes and the increase in number of transparent eyes, due to the eye drop containing the agent of the pre-sent invention.
EXAMPLES
The present invention will now be explained in the following embodiments.
As for experimental animals, senile accelerated mice aged 1 month (12 mice) and 5 months (12 mice) were used.
Both of the age groups were divided into three groups, in-dividually; Group 1 was given the solution of 0.05 mg/m1 1-hydrcxy-5-oxo-5H-pyrido(3,2-a)phenoxazine-3-carboxylic acid (general name; pyrenoxine) (the solution was ref erred to as pyrenoxine solution hereinafter); Group 2, both of the 40 organic germanium compound (1-1) solution (referred to as Ge solution) and pyrenoxine solution; Group 3 as the con-trol group, distilled water containing a suppressive agent on surface activity as a placebo solution. The administra-tion was carried out through eye drop, 4 times daily, 6 days /week. Before the initiation of eye drop, and 30, 60, 9O and 120 days after the initiation, mydriasis was induced using Midorin P (trade-mark) in each subject under the anesthesia of 0.7m1/kg of sodium nembutal intraperitoneally injected, before subjecting to lens observation under a stereomicroscope.
The lens observation in senile accelerated mice may be roughly classified into 4 items, i.e. transparency, forma-tion of concentric circles, distortion and cortical opacity in this example. By the term "transparency" is meant no ab-2~~'~~
normal symptom in lens so that retinal vessel can be ob-served through; by the term "formation of concentric cir-cles" is meant 2 to 5 rings are observed in concentric cir-cles in a lens; by the term "distortion" is meant the inci-dence of distortion in image on eyegrounds, because of ab-normal refraction of lens; by the term "cortical opacity"
is meant the incidence of wedge-like or diffuse opacity.
Two of such symptoms, formation of concentric circles and distortion were occurred in some lenses and in that cases, the symptom showing stronger change was selected as an ab-normal symptom.
1 The gye drox~ experiments startino at 1 month since birth The eyes of senile accelerated mice of age 1 month were examined prior to the administration of the eye drop.
Most of the eyes including those of the control group had transparent lenses without any abnormal symptoms; mild cor-tical opacity and no eye anophthalmia was simultaneously observed in one subject of Group 2 (a simultaneous adminis-tration group of Ge solution and pyrenoxine solution).
The examination which was carried out on day 30 after the initiation of eye drop demonstrated that the cortical opacity observed prior to the initiation of eye drop di.sap-geared. However, there occurred ring-like concentric cir-cles in one eye of Group 1 (pyrenoxine administration group), one eye of Group 2 (a simultaneous administration of Ge solution and pyrenoxine solution) and two eyes of Group 3 (as the control group). The examination on day 60 after the initiation of eye drop demonstrated that abnor-. .
mality in lens such as formation of concentric circles and distortion was observed in one eye of Group 1 and four eyes of Group 3.
The examination on day 90 after the initiation of eye drop demonstrated that the six eyes with transparent lens of Group 1, showed formation of concentric circles (in 4 eyes) and distortion (in two eyes), which indicated the oc-currence of cataract at initial stage. Of Group 3, four eyes with distorted lenses did not propose any change from the symptoms observed at the prior examination. On the con-trary, lenses of Group 2 were in good condition so that the lenses were thus diagnosed transparent.
The examination on day 120 after the initiation of eye drop demonstrated that distortion which was observed in two eyes of Group 1 on day 90 disappeared. Distortion disap-peared in one of the four lenses of Group 3, which had been diagnosed to be in distorted state. Such results indicate that distortion in lens may not generally be fixed. Of Group 2, one animal died during the experiments, but all of the other remaining mice were judged normal at this exami-nation.
The results heretofore mentioned are shown in TABLE 1 below: The ratios of each symptom to total are shown in FIGS. 1 through 3.
It might be said that these experiments verify the preventive effect of the agent of the present invention.

Symptoms Before eye drop On day 30 On day 60 initiation Dose group 1 2 3 1- 2 3 1 2 3 Number of eyes 6 7 4 6 7 4 6 7 4 Transparency 6 6 4 5 6 2 5 7 0 Formation of concentric 0 0 0 1 1 2 0 0 0 circles Distortion 0 0 0 0 0 0 1 0 4 Cortical 0 1 0 0 0 0 0 0 0 opacity Symptoms On day 90 On day 120 Dose group 1 2 3 1 2 3 Number of eyes 6 7 4 6 5 4 Transparency 0 7 0 0 5 0 Formation of concentric 4 0 0 6 0 1 circles Distortion 2 0 4 0 0 3 Cortical 0 0 0 0 0 0 opacity 2 The e~ drop experiments startina at 5 months since birth A trace of concentric circles in one or two rings be-gan to appear around lenses in the eyes of senile acceler-ated mice of age 5 months, but the transparency of their eyegraunds were judged good. As a result, they were tem-porarily judged to be transparent lenses before the initia-tion of eye drop.

The examination which was carried out on day 30 after the initiation of eye drop demonstrated the clear concen-trio circles in two lenses of Group 2 and four lenses of Group 3, but the eyes of Group 1 did not show any change.
The examination on day 60 after the initiation of eye drop demonstrated that Groups 1 and 2 showed good progress such that all eyes of the mice were judged transparent, and that formation of concentric circles accompanied with dis-tortion were induced in four eyes of Group 3.
The examination on day 90 after the initiation of eye drop demonstrated concerning Groups 1 and 2, the occurrence of severe change inducing formation of concentric circles (in 12 eyes) and distortion (in 2 eyes). Of Group 3, four j, eyes were diagnosed to have distortion and intense change in the lenses thereof.
The examination on day 120 after the initiation of eye drop demonstrated the formation of concentric circles in all of the lenses of Groups 1 and 2 (14 lenses); in partic-ular, the tendency of exacerbation accompanied by distor-tion was observed in 4 eyes of Group 1 (pyrenoxine adminis-tration group). On the other hand, of Group 3 as the con-trol group, distortion disappeared in one of the four eyes accompanied by distortion. However, the occurrence of cor-tical opacity was observed in a different eye, indicating the further progress of cataract.
The results heretofore mentioned are shown in TF~BLE 2 below. The ratios of each symptom to total are shown in FIGS. 4 through 6.

~~~'~6~
It might be said that these experiments verify the ef-fects of the agent of the present invention, on preventing the progress and the treatment.

Symptoms Beforeeye drop On day30 On day 60 initiation Dose group1 2 3 1 2 3 1 2 3 Number 8 4 6 8 4 6 8 4 of eyes Transparency6 8 4 6 6 0 6 8 0 Formation of concentric0 0 0 0 2 4 0 0 0 circles Distortion0 0 0 0 0 0 0 0 4 ' Cortical 0 0 0 0 0 0 0 0 0 opacity Symptoms On day 90 On day 120 Dose group 1 2 3 1 2 3 Number of eyes 6 8 4 6 8 4 Transparency 0 0 0 0 0 0 Formation of concentric ~ 8 0 2 8 1 circles Distortion 2 0 4 4 0 , 2 Cortical 0 0 0 0 0 1 opacity As is clearly demonstrated by above described Example, the effects on preventing or terminating the progress of cataract were observed in senile accelerated mice in Groups 1 and 2, compared with those of Group 3. Of the group given pyrenoxine solution alone, however, there were observed a small number of mice in which cataract was in advanced stage. That is, the above effects are not necessarily des-ignated absolute effects. On the contrary, of Group 2, namely the group given a combination of Ge solution and pyrenoxine solution, all the lenses remained transparent over a long period. Additionally to the above effects, there was obtained remarkable improving effects in that the lenses with severe symptoms such as cortical opacity recov-ered transparency.
Tn the above Example, even the other compounds except the compound (1-1), when administered, showed approximately identical effects as those described above.
Th present invention is as has been described and thus, the agent of the present invention is excellent as an agent for preventing and treating opacity of lens.

Claims (9)

1. An eye lens capacity preventing or treating agent that is a pharmaceutical composition containing eye lens opacity preventing or treating effective amounts of a pharmaceutically acceptable organic germanium compound represented by the formula:
[wherein R1, R2 and R3 each represent a hydrogen atom, a lower C1-4 alkyl group or a phenyl group; X represents a hydroxyl group, an O-lower C1-4 alkyl group, an amino group or O-Y+ {Y
represents a metal or are organic compound having a basic group}] and a cataract treating effective phenoxazine derivative.
2. The agent for preventing or treating opacity of eye lens according to claim l, which comprises 5 to 500 mg of the organo germanium compound and 0.005 to 0.5 mg of the phenoxazine derivative, each per 1 ml of the agent, the remainder being essentially water.
3. The agent for preventing or treating opacity of eye lens according to claim 2, wherein the organic germanium compound is represented by the formula:
(Ge - CH2 - CH2 - COOH)2O3 or (Ge - CH2 - CH2 - COOY)2O3 where Y represents an alkali metal.
4. The agent for preventing or treating opacity of eye lens according to claim 2, wherein the phenoxazine derivative is represented by the formula:
[wherein M is a hydrogen atom or an alkali metal].
5. The agent for preventing or treating opacity of eye lens according to claim 3, wherein the phenoxazine derivative is represented by the formula:
[wherein M is a hydrogen atom or an alkali metal].
6. The agent for preventing or treating opacity of eye lens according to claim 3 or 5 wherein the organic germanium com-pound is represented by the formula (Ge - CH2 - CH2 - COOY)2O3 where Y is sodium.
7. The agent for preventing or treating opacity of eye lens according to claim 4 or 5 wherein M in the formula for the phenoxazine derivative is sodium.
8. The agent for preventing or treating opacity of eye lens according to any one of claims 1 to 5, which is in an eye drop form further comprising one or more components selected from the class consisting of boric acid, sodium chloride, sodium hydroxide, benzalkonium chloride, .epsilon.-aminocaproic acid, methyl p-oxyaminobenzoic acid and chlorobutanol.
9. The agent for preventing or treating opacity of eye lens according to any one of claims 1 to 5, wherein the organic germanium compound and the phenoxazine derivative are separately prepared into formulations so that the resulting formulations are to be mixed for use as needed basis.
CA 2027665 1989-12-29 1990-10-15 Agent for preventing and treating opacity of lens Expired - Lifetime CA2027665C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP01-344590 1989-12-29
JP1344590A JP2816434B2 (en) 1989-12-29 1989-12-29 Prevention and treatment of lens opacity

Publications (2)

Publication Number Publication Date
CA2027665A1 CA2027665A1 (en) 1991-06-30
CA2027665C true CA2027665C (en) 2002-03-26

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CA 2027665 Expired - Lifetime CA2027665C (en) 1989-12-29 1990-10-15 Agent for preventing and treating opacity of lens

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CA (1) CA2027665C (en)

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JPH03206041A (en) 1991-09-09
JP2816434B2 (en) 1998-10-27
CA2027665A1 (en) 1991-06-30

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