Abstract:
Methyl methionine sulfonium salts having the formula ##STR1## wherein R -  represents an inorganic or organic anion are used in remedy for renal diseases and secondary hyper lipoidemia caused by renal diseases.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a medicine for renal diseases. 
     2. Description of the Prior Art 
     There has not been found perfect therapy for renal diseases. Certain steroids, immunodepressants, nonsteroid anti-inflammatory agents have been used as medicines for nephrotic syndrome. However, these medicines have various disadvantages. For example, the adrenocortical steroids cause slight side-effects of moon face, acne and transient increase of blood pressure and serious side-effects of gastric ulcer such as hematemesis and hematorrhea; infection, mental disorder and pituitary and renal cortex disfunctions. 
     The immunodepressants cause bone-marrow sanguification disfunction (anemia, leukopenia and blood platelet decrease) nausea, vomiting, liver disfunction, digestive organ disfunction such as stomatitis, skin rash, susceptibility to infections, low γ-globulinemia, herpes zoster, depilation etc.. 
     These diseases are caused by the renal disfunctions. 
     The non-steroid anti-inflammatory agents cause side-effects of digestive organ disfunction, latent infections and aggravation of infections, etc.. 
     The inventors have studied on medicines for renal diseases and have found that methyl methionine sulfonium salts are remarkably effective as medicines for renal disease nephrotic syndiome characterized by excessive urinary protein. 
     SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide a medicine for renal diseases and secondary hyper lipoidemia caused by renal diseases. 
     The foregoing and other objects of the present invention have been attained by providing a medicine for renal diseases and secondary hyper lipoidemia caused by renal diseases which comprises methyl methionine sulfonium salt having the formula ##STR2## wherein R -  represents an inorganic or organic anion as an active ingredient. 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The active ingredients of methyl methionine sulfonium salts used in the invention are the known compounds and have been used for gastro ulcer, duodenal ulcer, gastritis and hepatitis and can be produced by the process disclosed in Japanese Patent Publication No. 4757/1962 and the like. 
     The methyl methionine sulfonium salts can have the inorganic or organic anion. 
     Suitable inorganic anions include Cl - , Br - , I - , SO 4   --  etc. and suitable organic anions include carboxylic acid ions such as CH 3  COO -  and ##STR3## AND SULFONIC ACID IONS SUCH AS C 6  H 11  NHSO 3   -  (Cyclamic acid). 
     The optimum anions include Cl -  and I - . 
     Methyl methionine sulfonium chloride is especially preferable because of no hypersensity and economical reason. 
     The medicines for renal diseases of methyl methionine sulfonium salts can be applied by oral dose, intravenous injection and in the other conventional manner. 
     The dose of the methyl methionine sulfonium salt is dependent upon the kind and the severeness of renal diseases and is remarkably high, namely more than 200 mg usually 1000 to 2000 mg per one day in the oral dose for adult. 
     The methyl methionine sulfonium salts of the invention can be used in various forms such as tablet, capsule, injectable and the other medical forms. 
     The active ingredients of methyl methionine sulfonium salts can be applied together with the other medicines such as antibiotics, steroids, immunodepressants, diuretics, nonsteroid anti-inflammatory agents, etc.. 
     The characteristics of the methyl methionine sulfonium salts are effective for excessive urinary protein, hypercholesterolemia, and cause less side-effects and especially no serious side-effect. Accordingly, the methyl methionine sulfonium salts are remarkably effective for renal diseases for a long term therapy with or without the other medicine such as steroids and immunodepressants. 
     EXPERIMENT 1 
     Clinical Test 
     Methyl methionine sulfonium chloride was administrated to 45 patients having excessive urinary protein at a dose of 150 to 1800 mg/day with or without the other medicines shown in Table 1, singly or in combination with the additional medicines shown below. 
     When used in combination, the additional medicines were dosed in the amount usual for each of such additional medicines. 
     The amount of urine protein was measured for the clinical tests. The elimination or remarkable degree of reduction of urine protein was considered to be effective. As the result, 32 cases among 45 patients were effective and the side-effect was only one diarrhoea. 
     The non-steroid anti-inflammatory agents such as Ibuprofen, Indomethacin, Azapropazone, and steroids such as Predonizolone and antibiotics such as Cephalexin, methyl chlorophenyl iso-oxazolyl penicillin were used as the additional medicines. 
     
                       Table 1______________________________________                                Addi-       Dose         Urine protein                                tional              Dis- (mg/ Term  Be-   Af-   medi-No.  Age    Sex    ease day) (day) fore  ter   cine______________________________________1    32     ♀              R-1  1200 18    ±  -     Add.2    22     ♀              R-2  1000 84    ++    +3    56     ♀              R-3  1200 14    +     -4    10     ♂ R-4  600  21    +     -     Add.5    49     ♀              R-5  1200 147   +     ±  Add.6    35     ♂ R-6  300  70    ±  -7    48     ♀              R-7  1200 329   ++    +     Add.8    26     ♀              R-8  300  231   ±  -9    15     ♀              R-9  150  14    +++   +10   35     ♀              R-10 1200 14    ++    +     Add.11   55     ♂ R-11 1200 371   ++    +     Add.12   11     ♂ R-12 900  21    ±  -13   68     ♀              R-13 300  42    ++    -     Add.14   61     ♂ R-14 300  14    +     -     Add.15   75     ♂ R-15 300  119   +++   +16   76     ♂ R-16 300  35    ±  -17   39     ♀              R-17 300  42    ++    -     Add.18   53     ♀              R-18 300  49    ±  -19   26     ♀              R-19 1200 14    ±  -20   72     ♀              R-20 1200 54    ±  -21   23     ♀              R-21 1200 98    ++    -     Add.22   22     ♀              R-22 750  42    +     -23   23     ♂ R-23 750  24    ++    +24   18     ♀              R-24 750  90    ++    +25   27     ♂ R-25 750  28    ++    +26   25     ♂ R-26 600  35    ±  -27   21     ♀              R-27 750  29    ±  -28   37     ♀              R-28 1800 42    +     -     Add.29   27     ♂ R-29 1800 140   +++   ++    Add.30   23     ♂ R-30 1800 112   +     -31   22     ♂ R-31 1800 196   ++    +     Add.32   53     ♀              R-32 1800 70    +     -______________________________________ R-1: subacute nephritis R-2: nephritis R-3: right nephritis R-4: child nephritis R-5: gout nephritis R-6: pyelonephritis R-7: pyelitis R-8: chronic pyelonephritis R-9: pyelitis R-10: wandering right kidney R-11: renal sclerosis R-12: excessive urinary protein R-13: bladder tumor R-14: prostatic gland hypertrophy R-15: R-16: R-17: pyelitis R-18: light nephritis R-19: wandering right kidney R-20: right pyelitis R-21: nephrotic syndrome R-22: chronic nephritis R-23: R-24: nephrotic syndrome R-25: R-26: R-27: R-28: acute glomerulone phiritis R-29: nephrotic syndrome R-30: R-31: R-32: 
    
     EXPERIMENT 2 
     Therapy for Aminonucleoside nephrose 
     SD type male rats (weight about 100 g) were fed in each individual room of a metabolism cage under the free water and feed supply. 
     The rats were classified as the normal group for eight rats, the renal disease group for eight rats and the therapy group for eight rats. 
     0.3% Aminoucleoside aqueous solution (hereinafter referring to as AN) was administrated by intramuscular injection at a dose of 0.3 ml per 100 g of the rat. 
     The administration was continued from the 1st day to the 14th day at one time per day. 
     For the therapy group, methyl methionine sulfonium chloride was administrated by the oral dose at a dose of 1000 mg/kg (in a form of 1.0 ml per 100 g of the weight of rat) at one time per day for 10 days with AN from 5th day when the increase of the amount of urine protein was found. 
     The results of urine and blood biochemical observations are shown in Table 2 and Table 3. 
     The data in Tables are average value for eight rats in each group. 
     The difference between the renal disease group and the therapy group was significant. The symbol * means the existence of significant difference in 5% of the level of significance and the symbol (*) means the existence of significant difference in 5 to 1% of the level of significance. The symbol -- means non-significant difference. 
     
                       Table 2______________________________________            Renal     Normal disease  Therapy  Significant     group  group    group    difference______________________________________Weight (g)  180      196      176  *Urine amount(ml/day)    9.4      8.5      6.9  (*)Urine pH    6.7      6.5      6.2  (*)Urine protein (g/dl)       0.6      5.2      4.0  *Urine protein (mg/day)        54       441      294  *Urine albumin(g/dl)      0.1      2.4      1.6  *Urine albumin(mg/day)    6.6      196      106  *Urine Na (m Eq/l)       160      54       109  *Urine K (m Eq/l)       230      204      210  --______________________________________ 
    
     
                       Table 3______________________________________         Nor-    RenalSerum biochemical         mal     disease Therapy                                SignificantTest          group   group   group  difference______________________________________Total protein (g/dl)         6.48    3.60    4.47   *Albumin (g/dl)         2.60    0.49    1.25   *Albumin/Globulin ratio         0.68    0.16    0.41   *Cholesterol (mg/dl)         84.3    277     149    *Glycose (mg/dl)         169     135     138    --Urea nitrogen (mg/dl)         25.2    44.8    23.8   *Na.sup.+ (m Eq/l)         134     135     134    --K.sup.+ (m Eq/l)         5.1     5.4     5.6    --______________________________________ 
    
     The results in Tables 2 and 3 show that the methyl methionine sulfonium salt of the invention is effective for the renal disease. 
     EXPERIMENT 3 
     Therapy for hetero antikidney serum nephritis 
     Wister type male rats (weight of about 180 g) were classified as the normal group, the renal disease group and the therapy group(dose of 1000 mg/kg per day of methyl methionine sulfonium chloride) and were fed in each individual room of a metabolism cage. 
     Antikidney serum (rabbit) prepared in accordance with the Heymann method was intravenously injected into tail vein at a dose of 0.5 ml per 100 g of rat at one time per day. 
     The methyl methionine sulfonium chloride was administrated by oral dose for 9 days from one day before the injection. 
     The results are shown in Table 3. 
     In Table 3, the symbols for tissue observation mean the following conditions of tissues. 
     A: proliferation of polymorphs of glomeruli 
     B: thrombus formation 
     C: thickning of the basement membrane of the glomerular capillaries 
     D: obliteration of the glomerular capillary loops 
     E: anemia 
     F: exudate in Bowman&#39;s subcapsule space 
     G: thickning of Bowman&#39;s capsule 
     H: crescent formation of glomeruli 
     I: proteinaeous fluid in the tubli 
     J: swelling of tublar epithelium 
     K: proliferation of interstitial tissue cells 
     In Table 4, the degree of lesions were rated as follows: 
     0: no lesion of tissue is found; 
     0.5: slight lesion of tissue is found; 
     1: clear sporadic or slight lesion of tissue is found; 
     3: inflamed or clear lesion of tissue is found. 
     The average of ratings for 5 rats in each group is shown. 
     The level of significance was considered as the same with those of Table 1. 
     
                       Table 4______________________________________              Renal       Normal disease  Therapy  Signi-       group  group    group    ficance______________________________________Urine urea (mg/day)         6.3      121      104    --Urea nitrogen in blood(mg/dl)       23       25       24     --Observation of tissue A         0        1.4      0.5    (*)&#34;    B        0        1.1      0.1    *&#34;    C        0        1.7      0.4    *&#34;    D        0        1.7      0.3    *&#34;    E        0        2.2      0.1    *&#34;    F        0        0        0      --&#34;    G        0        1.1      0      *&#34;    H        0        1.1      0      *&#34;    I        0.6      1.8      0.8    (*)&#34;    J        0.5      1.6      1.3    --&#34;    K        0        0.2      0.3    --______________________________________ 
    
     The results in Table 4 show that the methyl methionine sulfonium salt of the invention is effective for the renal disease. 
     EXPERIMENT 4 
     Toxicity Test 
     Methyl methionine sulfonium chloride was dissolved in each distilled water at various concentration to give 0.2 ml per 10 g of mouse. 
     The test was carried out by the oral dose and the intraperitoneal injection of each solution in 10 ddY type male mice and 10 ddY femal mice. The results after 72 hours from the administration were observed. Probit analysis was used for statistical treatment of mortality. 
     The results are shown in Table 4. The low toxicity of methyl methionine sulfonium chloride was found. 
     
                       Table 5______________________________________Mouse     Dose           LD.sub.50 (mg/kg)______________________________________male      oral dose      11920female    &#34;              11255male      Intraperitoneal     injection       8139female    &#34;               7910______________________________________ 
    
     Composition 
     A 500 g of methyl methionine sulfonium chloride was uniformly admixed with 100 g of aluminum silicate and 350 g of corn starch (60 mesh sieve pass). 
     The mixture was charged into a kneader and 670 ml of 3% ethanol solution of hydroxypropyl cellulose was added into it, and the mixture was kneaded and was granulated by passing through a 16 mesh sieve and was dried by passing air at 45° C. 
     After drying the granules, the granules were passed through a 16 mesh sieve and was admixed with 16 g of magnesium stearate and 20 g of talc. 
     The mixture was treated by the tablet machine to form tablets having a diameter of 8 mm and a weight of 200 mg.