CHEMOTHERAPY

STUDIES ON SUSCEPTIBILITY OF CLINICALLY ISOLATED BACTERIAL STRAINS TO NITROFURAN DERIVATIVES

TETSUO TAKASHIMA, TOKUMITSU TANAKA, SUSUMU MITSUHASHI

1974 Volume 22 Issue 7 Pages 1133-1140
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1133

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Antibacterial activity of Panfuran-S, Panfuran acetate, Panazon, Furazolidone and Furadantin was investigated by using each 100 strains of Shigella, E. coli, Ps. aeruginosa, Proteus, Salmonella and S. aureus which were isolated from clinical specimens.
1. In 5 nitrofuran derivatives, Panfuran-S showed very strong antibacterial activity against bacterial strains tested.
2. Panfuran-S showed strong antibacterial activity against Shigella sonnei, Proteus morganii, and E groups ofSalmonella.
3. The bacterial strains highly resistant to Panfuran-S were not isolated from our survey during 10 years.
4. Cross resistance was observed between nitrofuran derivatives, but not observed between nitrofuran derivatives and TC, CP, SM, SA, KM and ABPC.
5.In vitro developed strains highly resistant to Panfuran-S were not demonstrated so far as examined, and in vitro developed resistance was found to be labile and decreased after several subcultures in nutrient broth.

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SENSITIVITY OFVIBRIO CHOLERAE (BIOTYPE EL TOR) TO PANFURAN-S

1. DRUG SENSITIVITIES OF V. CHOLERAE ISOLATED DURING THE PERIOD OF 1940-1971

TAKESHI YOKOTA, AKEMI FUJII

1974 Volume 22 Issue 7 Pages 1141-1145
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1141

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Drug sensitivities were examined by the plate dilution method for 103 strains of Vibrio cholerae (biotype El Tor), of which 72 and 31 strains had been isolated in India in 1940 and in Philippines in the period of 1969 to 1971 respectively. Strains resistant to chloramphenicol and/or tetracycline were found to be simultaneously resistant to streptomycin and sulfonamide, i. e. multiple drug resistant strains. Whereas, strains resistant to streptomycin or sulfonamide were not only multiple resistant but also single resistant strains. It was noteworthy that all tested strains of V. cholerae (biotype El Tor) were highly sensitive to Panfuran-S, regardless of multiple resistant or single resistant strains to other drugs.
It was confirmed that inoculum size of the test bacteria affected markedly on the minimum growth inhibitory concentrations of sulfonamide and Panfuran-S but not of chloramphenicol, tetracycline and streptomycin.

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BACTERIOLOGICAL AND MORPHOLOGICAL STUDIES ON ANTIBACTERIAL ACTIVITIES OF DIHYDROXYMETHYL-FURATRIZINE

MASAATSU KOIKE, KYOKO IIDA, KOICHI NAKASHIMA

1974 Volume 22 Issue 7 Pages 1146-1152
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1146

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Antibacterial activities of dihydroxymethyl-furatrizine againstEscherichia coli B and Staphylococcus aureus 209 P were investigated and morphological alterations of the drug-treated cells were examined by scanning and transmission electron microscopy. Difference between the action of the drug E.coli and against Staph, aureus was clearly indicated in this experiment : The drug exerts the bactericidal effect on E. coli, but bacteriostatic on Staph. aureus. Further, morphological alterations of the drug-treated cells were also quietly different between both bacteria. After several hours contact with sublethal dose of the drug, the cells of E. coli elongated up to 20-30μ, which was resulted from inhibition of dividing, and partially lysed, while in Staph. aureus, thiny cells with 0.3-0.5μ in diameter were produced by abnormal septation. From these results, the regulatory mechanism of the cell dividing may be possibly affected by this drug.

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THE STRUCTURE AND BIOLOGICAL ACTIVITIES OF 3-AMINO-6- [2- (5-NITRO-2-FURYL) VINYL] -1, 2, 4-TRIAZINE AND ITS DERIVATIVES : ON THE CURING ACTION OF THE AGENT ON DRUG RESISTANT BACTERIA

MUNEMITSU TOMOEDA, REIKO KITAMURA, MIDORI YAMADA, SACHIKO NAKAMURA, MA ...

1974 Volume 22 Issue 7 Pages 1153-1158
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1153

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A curing action of three 5-nitrofuran compounds, possessing similar substituents with a triazine nucleus or its oxidized form at 2-position is described on some E. coli K-12 strains harboring R 100-1 and R100 factors. Treatment of R⁺cells (10³-10⁹ cells/ml) with sublethal concentrations of FT-H, FT, FT-Ac in Penassay broth (pH 7.6) led to the loss of part or all of these genetic elements. FTH and FT were shown to induce the elimination of drug resistance of R⁺cells more efficiently than FT-Ac. Appearance of drug-susceptible variants among survivors was observed around when the viable count of R⁺cells decreased 10^-2-10^-3 in 3-6 hrs. Several types of segregants were formed as well as R^-cells. These segregants failed to transfer their R factors suggesting that transfer genes of their sex factors had mutated or had been deleted at least partly. Cml^s variants gave no revertants to drug resistance. FT-H and FT were reduced metabolically by R⁺cells more rapidly than FT-Ac. Mutagenicities of these compounds were parallel to their metabolic reduction rates. It is concluded that all the biological activities of nitrofurans are derived from their metabolic reduction potential. It is also suggested that since the agent is not more toxic to R⁺cells than R^- cells, the isolation of drug-susceptible variants under these conditions may be attributable to mutagenic actions of the agent.

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THE MODE OF ANTIBACTERIAL ACTION OF NITROFURAN COMPOUNDS

SABURO YAMAGISHI, YOSHINORI NAKAJIMA, YASUYO ISHIKAWA, KYOKO FUJII

1974 Volume 22 Issue 7 Pages 1159-1164
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1159

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The antibacterial activity of two nitrofurans, 3-dihydroxymethylamino-6- [2- (5-nitro-2-furyl) vinyl] -1, 2, 4-triazine (Panfuran-S : FT) and 2-[2-(5-nitro-2-furyl) vinyl] -quinoline (NFQ) was examined. The experimental results determining growth rates, viable counts (Fig. 1, 2, 4, and 5), and biomacromolecules (Fig. 3 and 6) in the presence of the nitrofurans suggested that the potent growth inhibitory action of these drugs againstEscherichia coliQ13 orStaphylococcus aureusE642-1 could apparently be associated with the interference of DNA synthesis. Mutants ofE. coli, such as the DNA polymerase I-deficient mutantPolAl and the recombination-deficient mutant rec A13, exhibited much higher sensitivity to the nitrofurans than the corresponding parent strains did (Fig. 7, Table 2 and 3). The results indicate the close relationship between the mechanism of inhibition by the nitrofurans and the ability to repair the DNA damage caused by these drugs in the bacterial strains.

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ABSORPTION, DISTRIBUTION AND EXCRETION OF NITROFURAN COMPOUNDS

AKIRA TAKAI, YOSHIFUMI NAKASHIMA, ETSURO SIMIZU, NOBUO TERASHIMA

1974 Volume 22 Issue 7 Pages 1165-1170
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1165

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Absorption, distribution and excretion of four nitrofuran compounds were studied in rats, using¹⁴C-labeled materials.
(1) When 10 mg/kg of these nitrofuran compounds were administered orally to rats, expected absorption percentage were as follows, 1, 5-bis (5-nitro-2-furyl) -1, 4-pentadiene-3-one amidinohydrazone hydrochloride (PZ) : 2-4%, 3-amino-6- (2- (5-nitro-2-furyl) vinyl) -1, 2, 4-triazine (FT-H) and 3-di (hydroxymethyl) amino-6- (2- (5-nitro-2-furyl) vinyl) -1, 2, 4-triazine (FT) : 40-50%, and 3-acetamido-6- (2- (5-nitro-2-furyl) vinyl) -1, 2, 4-triazine (FT-Ac) : about 20%.
(2) The plasma level of radioactivity reached maximum within 1 hour for¹⁴C-FT-H or 2 hours for¹⁴C-FT and ¹⁴C-FT-Ac after oral administration, and then disappeared rapidly.
(3) The distribution of ¹⁴C-labeled nitrofuran compounds in rats tissues showed comparativery higher levels in kidney, liver, bladder, stomach and intestine, and lower in pancreas, spleen, adrenal, heart, lung, testis, fat, muscle, brain and eye ball, and most of them were found to be practically negligible at 24 hours after oral administration.
(4) Excretion studies showed that the radioactivity of these¹⁴C-labeled nitrofuran compounds were excreted completely within 120 hours after oral administration.

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EVALUATION OF CARCINOGENIC ACTIVITY OF 3-DI (HYDROXYMETHYL) AMINO-6- (5-NITRO-2-FURYLETHENYL) -1, 2, 4-TRIAZINE (DIHYDROXYMETHYL-FRATRIZINE, PANFURAN-S) IN FEMALE RATS

AKIRA TAKAI, TOYOAKI YONEDA, HIROKO NAKADA, GOROKU OHTA

1974 Volume 22 Issue 7 Pages 1171-1179
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1171

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0.1% 3-Di (hydroxymethyl) amino-6- (5-nitro-2-furyletheny1) -1, 2, 4-triazine (dihydroxymethyl-furatrizine, Panfuran-S ®) -and 0.03% 2-acetylaminofluorene-containing diets were given respectively to Wistar female rats for 80 weeks.
Out of 41 control rats, spontaneous tumors were noted to develop in 13 rats as the time of sacrification : fibrima or fibroadenoma of the breast (3 rats), squamous cell carcinoma of the external ear duct (1), adenoma of anterior lobe of the hypophysis (1), sarcoma of the liver (2), cystoma of the ovary (4) and cystoma of the subcutaneous tissues (2).
Of 48 rats fed dihydroxymethylfuratrizine, 9 rats were found to have tumors in various organs : sarcoma or adenocarcinoma of the small intestine (3), fibroma or fibroadenoma of the breast (4), adenocarcinoma of the uterus (1) and cystoma of the ovary (1).
Of 36 rats given 2-acetylaminofluorene, 34 rats were observed to have tumors in many organs : hepatoma or adenoma of the liver (29), benign or malignant tumors of the breast (9), squamous cell carcinoma of the external ear duct (6) and others.
It appears that dihydroxymethyl-furatrizine has no carcinogenic activity when Wistar female rats were used for a period of 80 weeks, compared with both non-treated control rats and positive control rats.

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EVALUATION ON THERAPEUTIC EFFECTS OF A NITROFURAN DERIVATIVE AND SEVERAL ANTIBIOTICS FOR EXPERIMENTAL SALMONELLOSIS IN MICE

HIROSHI ZEN-YOJI, TAKESHI TERAYAMA, NOBUYUKI IKEJIMA, TAKASHI ONOGAWA

1974 Volume 22 Issue 7 Pages 1180-1188
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1180

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Comparative studies were made on the therapeutic effects of several antimicrobial agents, such as Panfuran-S (FT), Chloramphenicol (CP), Kanamycin (KM), Aminobenzylpenicillin (ABPC) and Cephaloridine (CER), for experimental salmonellosis in mice infected with an avirulent variant strain of Salmonella enteritidis, RB₁.
Of them, FT was found to have the most significant therapeutic effect (P<0.01-0.05), when more than 0.5 mg of the drug per mouse once a day was administrated orally at 0 and 24 hours after the infection. KM exhibiting the effect next to FT was effective only when it was administratedvia the intramuscular route immediately after infection, however, it was no longer effective if it was administrated 24 hours after the infection. None of the CER, ABPC and CP showed therapeutic effect on experimental salmonellosis in mice.

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HISTOPATHOLOGICAL STUDY OF THERAPEUTIC EFFECT OF FT (DIHYDROXYMETHYL-FURATRIZINE) AND OTHER ANTIBIOTICS IN EXPERIMENTAL SALMONELLOSIS

KOHJI FUKAI, KEIKO YANAI, KAORI HONMA

1974 Volume 22 Issue 7 Pages 1189-1192
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1189

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The therapeutic effect of FT and other antibiotics administered to the mice in experimental Salmonellosis was histologically evaluated. The judgement of the effect was made according to the presence, size and kind of typhoid nodules produced in the animal's livers.
As a result, it was found that the FT-treated group showed the best therapeutic effect forming the least nodules, with the KM-treated group second on the list. But the effects of KM and the others were found far less than that of FT.

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COMBINATION PANFURAN-S AND KANAMYCIN THERAPY IN ACUTE INFECTIOUS ENTERITIS

YOSHIO MATSUBARA, SHINICHIRO UKAI, TATSU IIMURA, TOKUO YANAGISHITA, NA ...

1974 Volume 22 Issue 7 Pages 1193-1200
Published: September 25, 1974
Released on J-STAGE: March 08, 2011

DOIhttps://doi.org/10.11250/chemotherapy1953.22.1193

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Combination Panfuran-S (FT) and Kanamycin (KM) therapy was administered to 120 patients with dysentery and suspected dysentery to examine its effectiveness in bacterial elimination.
1) As a result of the administration of combination FT and KM therapy to 51 patients with bacillary dysentery and Shigella carriers, the causative organisms disappeared in all cases by the 4th day of administration and no reappearance of the organisms was observed. The FT-KM group was slightly more effective in the disappearance of organisms than the KM-NA group used as the control.
2) A study on the clinical effects of FT-KM therapy in 26 patients with diarrhea in which cultures were negative and 51 patients with bacillary dysentery showed that it took a little longer period of treatment for symptoms to disappear in the KM-FT group than in the KM-NA group.
3) In 8 patients with Salmonella enteritis, KM-FT combination therapy showed good effectiveness in bacterial elimination with an efficacy rate of 88.3%.
4) The therapy showed good effectiveness in 14 cases of Vibrio parahemolyticus enteritis.
5) Vomiting was observed as a side-effect in 2 out of 120 cases.

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