Radiosensitizing and toxic action of metronidazole and isometronidazole (1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole) on the cells of Ehrlich ascites cancer and hemoblastosis La in vitro

A study was made of Ehrlich ascites tumor growth and life span of mice bearing hemoblastosis La after inoculation of tumor cells subjected, in anaerobic conditions, to the effect of gamma-radiation and/or metronidazole and isometronidazole. It was shown that the cytotoxic effect of isometronidazole was less manifest than that of metronidazole the radiosensitizing effect, with a reference to anoxic tumor cells in vitro, being nearly the same.     

Action of hypoxic sensitizers on the survival of haplont yeasts irradiated with ionizing radiation

A study was made of the oxygen effect and the radiosensitizing action of metronidazole and misonidazole on hypoxic cells of irradiated yeast haplonts. It was shown that metronidazole did not increase the radiosensitivity of all the strains under study while the sensitizing effectiveness of oxygen and misonidazole approximated the values characteristic of different repair-deficient rad-mutants. Possible causes of the radiosensitizing effects observed are discussed.     

Increase in the effectiveness of irradiating sarcoma-45 in rats using metronidazole

A single exposure to ionizing radiation combined with the administration of metronidazole accelerated the regression of sarcoma-45 and increased the number of animals with fully regressed tumors as compared to control rats exposed to radiation alone. The maximum effect was registered when tumors were irradiated 90 min after the administration of metronidazole. With fractionated irradiation the radiosensitizing effect of metronidazole was less pronounced.     

Radiosensitizing and toxic effect of metronidazole and its ortho-isomer 1-(2-hydroxyethyl)-2-methyl-4-nitroimidazole on Escherichia coli B/r cells

A study was made of the effect of metronidazole and isometronidazole on the survival rate of irradiated and nonirradiated E. coli B/r cells. These substances had similar radiosensitizing activity with regard to anoxic cells and did not sensitize cells irradiated in the air. At the same time, isometronidazole was found to be less toxic than metronidazole.     

Combined effect of interferon inducers, radiosensitizing and antineoplastic agents on solid tumors

In experiments with mice bearing solid sarcoma 37 a study was conducted on the combined effect of radiation and inductors of endogenous interferon synthesis (IEIS), together with hyperthermia or together with an alkylating and carbomoilating agent, dimethinur. The effect was estimated by the tumor growth coefficient and by the number of animals with the regressed tumors. Po I. polyC was not shown to influence the efficiency of hyperthermia combined with radiation; dextransulphate and tiloron increased the radiosensitizing effect of hyperthermia. Dimethinur aggravated the effect of radiation, but with IEIS used together with dimethynur and radiation, the response of the tumor increased insignificantly as compared to the effect of IEIS together with radiation.     

Reactions of nitroimidazoles with free radicals--enhancement of reaction by u.v. irradiation

The free-radical reactivity of the nitroimidazole derivatives metronidazole, misonidazole, benznidazole and ornidazole was investigated by observing their effect on the polymerization of acrylamide in aqueous solution. Free-radical polymerization was initiated by the thermal decomposition of potassium peroxydisulphate at 50 degrees C. Measurement of the polymerization rate showed an inhibitory effect of the nitroimidazoles which was greatly enhanced when the system was irradiated with u.v. light near their absorption maximum of 320-325 nm. Analysis of the competitive kinetics of the system enabled calculation of the rate constant for reaction of the ground state and photoexcited nitroimidazole with the polyacrylamide free radicals. No significant difference between the various nitroimidazoles could be found in the dark reaction, but in the u.v.-irradiated system the order of reactivity (misonidazole greater than benznidazole greater than metronidazole approximately equal to ornidazole) was the same as the reported relative mutagenic, cytotoxic and radiosensitizing potency of the compounds. These results imply that the excited states of the nitroimidazoles are important to their activity in radical-radical reactions.     

Interferon-inducing activity of an immunotherapeutic anticancer agent, SSM, prepared from Mycobacterium tuberculosis strain Aoyama B

The interferon-inducing capacity of arabinomannan-lipid preparation (SSM) extracted from Mycobacterium tuberculosis Aoyama B in both BCG-sensitized and unsensitized mice was studied in comparison with that of purified protein derivative (PPD) prepared from the same tubercle bacillus. Although it is known that PPD cannot stimulate interferon production in BCG-unsensitized mice, interferon activity was found in sera of both groups of mice after intravenous injection of SSM at a dose of 5 mg/kg. The maximum titer was detected 5 hr after injection. The interferon induced by SSM in both groups of mice shared certain physicochemical properties with the immune interferon induced by PPD in BCG-sensitized mice. In BCG-unsensitized mice, interferon induction by SSM was markedly inhibited by pretreatment with trypan blue and carrageenan, whereas it was not depressed in BCG-sensitized mice given the same treatment or when interferon was induced by PPD. In addition, induction of interferon in BCG-sensitized mice by SSM and PPD and in unsensitized mice by SSM was completely abrogated by pretreatment with hydrocortisone acetate and whole-body x-irradiation (700 R). These results suggest that in BCG-unsensitized mice macrophages, in addition to X-ray or hydrocortisone-sensitive cells, may be required for interferon induction by SSM.     

Therapeutic efficacy of moxifloxacin in a murine model of severe systemic mixed infection with Escherichia coli and Bacteroides fragilis

The therapeutic efficacy of moxifloxacin was studied in an experimental murine model of a systemic aerobic/anaerobic mixed infection and compared to therapies with either imipenem or ciprofloxacin plus metronidazole. Groups of 20 mice each were intravenously (iv) infected with approximately 2.5 x 10(6) colony forming units (CFU) of Escherichia coli and 2 x 10(7)CFU of Bacteroides fragilis. Iv therapy was started 24 h post-infection (pi) with either moxifloxacin, imipenem, or ciprofloxacin plus metronidazole, for 3 days. A control group of 20 mice was left untreated. Survival rate at day seven pi was recorded, mice were then sacrificed and bacterial organ contents of livers and kidneys were determined. All mice treated survived at day seven, while six animals of the untreated group died. B. fragilis was not detected in any of the treated mice. E. coli was found in two of the moxifloxacin-treated mice and in two and five of the ciprofloxacin plus metronidazole and imipenem-treated animals, respectively. The results indicate that a therapy of severe mixed aerobic/anaerobic infections with moxifloxacin might be feasible and possibly be as efficacious as current therapy regimens with ciprofloxacin plus metronidazole or imipenem.     

抗生素在体内外对厌氧菌和艰难梭菌细胞毒素生成的作用

氯林霉素、灭滴灵和甲砜霉素对大多数肠道厌氧菌的生长具抑制作用。氯林霉素还会破坏肠道菌群平衡,使原来受抑制的艰难梭菌得以定植,并在艰难梭菌浓度达10~8/g盲肠内含物时,检测到艰难梭菌细胞毒素。培养基中亚抑菌浓度的氯林霉素和灭滴灵会推迟艰难梭菌细胞霉素的生成。灭滴灵还可保护无菌小鼠及受氯林霉素处理的悉生小鼠免遭艰难梭菌细胞毒素的致死作用,从而证实了灭滴灵在伪膜性结肠炎临床治疗中的可用性。     

Free-radical formation in gamma-irradiated oriented DNA containing electron-affinic radiosensitizers.

Electron paramagnetic resonance (e.p.r.) was used to study the free radicals induced by gamma-irradiation at 77 K in oriented DNA with incorporated electronaffinic radiosensitizing compounds (4-nitroacetophenone, metronidazole, and Ro-07-0582). The observed e.p.r. spectra were compared with those obtained from pure oriented DNA, which had previously been analysed in detail and found to consist mainly of two components, arising from anion redicals on thymine, and cation radicals on guanine. The major spectral changes caused by the radiosensitizers could be explained as a considerable increase in the formation of cationic free radicals on guanine. There were also indications of the formation of anion radicals on the radiosensitizer molecules. No hydrogen-addition free radicals on thymine were observed when the radiosensitized samples were annealed, in contrast to the pure DNA samples.     

Effect of metronidazole on the free thymidine content in the blood serum of irradiated mice

The influence of a radiosensitizer, metronidazole, on the free thymidine content of blood serum of irradiated mice was studied in aerobic and hypoxic conditions. A heated metronidazole solution (1 mg/g) was administered intraperitoneally 30 min before irradiation of animals with a dose of 3 Gy. Thymidine concentration in blood serum was determined by the radioimmunological technique. The influence of metronidazole on the level of thymidinemia was only noted in the animals exposed under hypoxic conditions.     

Effect of metronidazole and local irradiation of the tumor on paramagnetic metal complexes of the liver and tumor tissues

A study was made of changes in the intensity of the ESR signals in tissues of sarcoma-37 and liver of mice after radiation of the tumor, administration of metronidazole, and after the combined effect of the two factors. The most pronounced changes in the ESR signals were induced by metronidazole. An appreciable increase in the content of nitrosyl complexes in the tumor was noted after the combined effect of metronidazole and radiation which was indicative of the radiation-induced formation of a large number of metronidazole anion-radicals in the tumor.     

Radiosensitizing activity and metabolism of nitrofuran derivatives. Preparation M-106

It was shown that the preparation of a nitrofuran M-106 series exerts a radiosensitizing effect on tumors with contact application. The observed effect is practically absent after noncontact administration of the preparation. On the basis of the data obtained from studies of M-106 metabolism in microsomes of liver and Ehrlich ascites tumor cells of mice it is concluded that the intact form of the preparation is responsible for the radiosensitizing effect, and that the absence of this effect with the noncontact administration is due to its low concentration in the tumor because of the active metabolic transformation of M-106 in the animal liver.     

Interferon and Host Resistance to Rauscher Virus-induced Leukemia

A random bred strain of mice (CD-1) was shown to develop resistance to Rauscher leukemia virus (RLV) as the animals matured. Resistant adult mice developed relatively high-serum levels of interferon (150 to 2,000 units per ml) in contrast to susceptible 21-day-old animals in which interferon levels were undetectable or low (less than 20 to 200 units per ml). A similar correlation between resistance and interferon levels was observed in comparisons between resistant CD-1 and susceptible BALB/c mice. The F(1) hybrids of CD-1 x BALB/c and BALB/c x CD-1 matings manifested an intermediate degree of susceptibility and interferon production. The difference in interferon production by CD-1 and BALB/c mice was specific for the RLV-host interaction, since both strains produced equal serum levels of interferon in response to Sindbis and Newcastle disease viruses. The mortality of CD-1 suckling mice infected with Rauscher leukemia virus was decreased by treatment with interferon. These data demonstrate an association between interferon production by the host and the observed relative resistance of the CD-1 strain of adult mice to the subsequent malignant transformation. This virus-host relationship provides an excellent model for further study of factors affecting the development of virus-induced leukemia.     

Effect of hypoxic cell sensitizer metronidazole on the radiation reaction of clonogenic cells from solid tumors

The clonogenic capacity of cells from peripheral and central zones of solid NKLy tumors of mice treated with metronidazole, a sensitizer of hypoxic cells, and with a mixture of metronidazole and radiation was studied by cloning in diffusion chambers. The cytotoxic effect of metronidazole was only noted during the prolonged interaction with cells under acute hypoxia that was observed in central tumor zones. Metronidazole increased by more than two times the radiosensitivity of cells from the central zones of the tumor and did not influence the radiation response of cells from the peripheral zones. Metronidazole was shown to inhibit the repair of potentially lethal radiation damages.     

Effect of antimicrobial therapy on bowel flora and bacterial infection in irradiated mice

Mice exposed to 10 Gy cobalt-60 radiation were given intramuscular antimicrobial therapy of gentamicin, or metronidazole, or a combination of the two. Mortality in the mice treated with metronidazole alone or in combination with gentamicin occurred earlier than in the controls (P less than 0.001). Microorganisms were recovered from the blood, spleen, and liver of the metronidazole-treated mice earlier than from other groups. The predominant organisms recovered from these animals were Enterobacteriaceae. Quantitative cultures of the ileal flora showed a decrease in the number of aerobic, facultative anaerobic and strict anaerobic bacteria after irradiation, and a subsequent increase only in the number of strict aerobic bacteria. As compared to untreated mice, a rapid decrease (by 8.8 logs) in the number of anaerobic flora occurred in the mice treated with metronidazole 5 days after irradiation. This was followed by a rapid increase in the number of aerobic organisms which coincided with the earlier mortality in this group. These data suggest that antimicrobial agents that decrease the number of the strict anaerobic component of the gut flora enhance systemic infection by aerobic or facultative anaerobic bacteria, and this facilitates mortality after irradiation.     

Metronidazole-induced susceptibility of adult mice to intestinalClostridium botulinum colonization

Clostridium botulinum type A spore challenges were given orogastrically to adult mice that had been treated with metronidazole. The organism multiplied in the intestinal tract for up to five days if it was administered 9–48 h after the last dose of metronidazole. The known antibacterial spectrum of metronidazole indicated that obligate anaerobic bacteria are important in the natural resistance of adult mice to colonization byC. botulinum, but treatment with the antimicrobial agent did not reduce the number of these bacteria in the cecum and colon.     

Modification of the action of ionizing radiation on cells of transplantable tumors by administering xanthobine

In experiments on mice it was established that the radiosensitizing effect of xanthobin was manifested by the enhancement of the inhibiting action of ionizing radiation on the growth of adenocarcinoma RL-67, diminution of the "shoulder" of the survival curve of Ehrlich ascites tumor cells, and increase in the average life of tumor-bearing animals.     

阴道白假丝酵母菌过度增殖的小鼠模型建立

目的建立阴道白假丝酵母菌过度增殖的小鼠模型。方法甲硝唑溶液（浓度为12．5mg／mL）30μL注入小鼠阴道内,1次／d,连续5d,白假丝酵母菌菌液（1×10^8CFU／mL）30μL接种到小鼠阴道内,1次／d,连用5d。取阴道冲洗液进行阴道菌群分析,并做阴道组织标本电镜观察。结果模型组小鼠阴道内白假丝酵母菌活菌数显著增加,乳杆菌活菌数量显著下降（P〈0．01）,出现阴道红肿、分泌物多和黏膜充血等白假丝酵母菌过度增殖的典型症状。结论通过抗生素脱污染后,小鼠阴道内接种白假丝酵母菌,能在小鼠阴道内定植,成功建立阴道白假丝酵母菌过度增殖的小鼠模型。     

Increase in the sensitivity of leukemia cells, incubated in interferon, to the effect of immune serum]

L-1210 AND P-388 leukemic cells were incubated in three types of interferon, i.e. L-cell interferon and two types of lymphocyte interferon (induced in the lymph node lymphocytes of intact mice and the lymphocytes obtained on the 10th day after intraperitoneal injections of 5-10(7) L-1210 cells). "False" interferon obtained by the method analogous to that of obtaining L-cell interferon, excluding the viral induction, was used for control. Cells incubated in interferon proved to be more sensitive to the action of the cytotoxic antibodies than those treated with "false" interferon. Treatment of the cells with lymphocytic interferon induced on the lymphocytes of immune mice increased their sensitivity even more in comparison with the cells treated with interferon obtained from intact mice.