Mutagenesis, Vol. 17, No. 1, 31-35,
January 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
Cytogenetic analysis of peripheral blood lymphocytes of children treated with nitrofurantoin for recurrent urinary tract infection
yt
,21
Department of Botany and Genetics, Vilnius University, 21 
uirlionis Street, 2009 Vilnius, Lithuania and
1 Department of Pediatrics, Vilnius University Children's Hospital, Vilnius University, 7 Santarikiu Street, 2600 Vilnius, Lithuania
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The objective of this study was to determine whether nitrofurantoin, used for long-term antimicrobial prophylaxis of urinary tract infection, may induce chromosome aberrations (CAs) and sister chromatid exchanges (SCEs) in lymphocytes of treated children. Ninety-nine blood samples were taken from 69 children aged from 0.2 to 13 years and suffering from urinary tract infection. The treatment consisted of oral administration of nitrofurantoin at doses of 5–8 mg/kg/day for the first 7 days and at doses of 1–2 mg/kg/day for the rest of the treatment period. Blood was sampled before the start of the nitrofurantoin therapy and after 1, 3, 6 and 12 months of the therapy. Analysis of variance showed no statistically significant increase in CA and SCE frequencies in lymphocytes of children treated with nitrofurantoin for 1–12 months. However, a significant increase in SCE rates was determined in lymphocytes of those patients whose blood samples were available both before and after treatment with nitrofurantoin (6.21 ± 0.28 and 7.30 ± 0.39 SCE/cell, respectively, P = 0.0315, Student's paired t-test). Moreover, there was a statistically significant correlation (r = 0.6603, P = 0.0270) between cumulative dose of nitrofurantoin and SCE frequency in lymphocytes of children after 1 month of the therapy. Also, in vitro experiments indicated that nitrofurantoin was able to induce both CAs and SCEs in human lymphocytes. Positive findings with chromosome aberrations and SCEs in vitro and suggestive results with SCEs in vivo indicate that further, much larger follow-up studies are needed to elucidate the genetic safety of the therapeutic use of nitrofurantoin.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Urinary tract infection (UTI) is one of the most prevalent forms of infectious diseases among children. Recurrence of UTI is common in susceptible individuals, especially in those with vesico-uretheral reflux. Long-term low dose antimicrobial prophylaxis is often necessary in such patients. Nitrofurantoin [N-(5-nitro-2-furfurylidene)-1-aminohydantoin, CAS no. 67-20-9] has been used effectively in preventing recurrences of UTI for many years (Bollgren, 1999
). In many cases, nitrofurantoin is advantageous compared with other antimicrobial drugs (ampicillin and trimethoprim sulfamethoxazole) because of low nitrofurantoin resistance rates among pathogenic bacteria from urinary tract isolates (Zhanel et al., 2000). Long-term antimicrobial therapy with nitrofurantoin is generally considered safe for children (Uhari et al., 1996). However, an increased risk of transitional cell carcinoma in patients with a history of nitrofurantoin treatment was detected in one epidemiological case–control study (Steineck et al., 1995). Additionally, nitrofurantoin was clearly mutagenic in vitro for bacteria (Ni et al., 1987) and mammalian cells (Ishidate, 1988). Nitrofurantoin induced sister chromatid exchanges (SCEs), chromosome aberrations (CAs) and micronuclei in rodent bone marrow in vivo (Parodi et al., 1983; Thompson, 1986), but no induction of somatic gene mutations in mouse embryos or CAs in secondary spermatocytes was detected (Fonatsch, 1977; Gocke et al., 1983). The only study performed with humans showed that nitrofurantoin does not cause a detectable increase in SCE in lymphocytes of adult UTI patients (Sardays et al., 1990). It is not clear, however, how well these results may be extrapolated to pediatric patients, because of the marked differences in pharmacokinetics of nitrofurantoin in adults and children (Wierzba et al., 1982).
Thus, the present study was initiated to evaluate CA and SCE frequencies in lymphocytes of pediatric patients undergoing long-term nitrofurantoin therapy. CAs are now considered a good predictor of human cancer risk (Bonassi et al., 2000). SCEs were chosen due to their ability to detect nitrofurantoin genotoxicity in vivo (Parodi et al., 1983), however, they are not predictive of cancer risk (Bonassi et al., 2000). In vitro experiments with peripheral blood lymphocytes were also performed in order to test whether human lymphocytes are sensitive enough to detect genotoxicity of nitrofurantoin.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Patients
Sixty-nine children suffering from UTI and hospitalized in Vilnius University Children's Hospital were included in the study. With parental consent, an extra 2 ml blood sample was obtained from the children when blood was collected for routine biochemical monitoring. The patients included 59 with chronic pyelonephritis (tubulo-interstitial nephritis) and 10 with chronic cystitis. Their ages ranged from 0.2 to 13 years, with a mean of 5.8 ± 0.3 years. The blood urea nitrogen and creatinine levels of all patients were within the normal range: blood urea nitrogen levels ranged from 3.0 to 6.9 mmol/l and creatinine from 0.03 to 0.08 mmol/l. Blood sampling was performed before the start of nitrofurantoin therapy (31 children, the control sample) and after 1, 3, 6 and 12 months of the therapy. Each sampling group consisted mainly of different patients, however, for 13 patients blood samples before treatment and after 1–12 months of the therapy were available. All patients had undergone X-ray examination (urethrocystography) prior to the start of therapy (effective dose equivalent for a procedure involving two film exposures was 0.4–2.4 mSv). As a contrast medium, Urografin 76% (Schering AG, Germany) was used. Twenty milliliters of Urografin 76% was diluted with 0.02% furacillin solution and administered to the urinary bladder utilizing a catheter. To evaluate possible cytogenetic effects of urethrocystography, 24 blood samples were taken from children with the same diagnosis before the X-ray procedure.
Treatment schedule
The treatment consisted of oral administration of nitrofurantoin at doses of 5–8 mg/kg/day for the first 7 days of treatment and at doses of 1–2 mg/kg/day for the rest of the treatment period. Twenty-six children were studied at diagnosis and had no previous medication. Others had received antibiotics, mainly ampicillin (50–100 mg/kg/day) or gentamicin (3 mg/kg/day), for periods of up to 7 days.
Cytogenetic procedures
Blood samples were obtained by venipuncture and collected into heparinized syringes. For each subject, three lymphocyte cultures were usually set up according to conventional techniques. Cultures were made in RPMI 1640 medium supplemented with 12% newborn calf serum, 7.8 µg/ml phytohemagglutinin, 100 U/ml penicillin and 100 µg/ml streptomycin. All reagents were purchased from Sigma (St Louis, MO). The cells were grown at 37°C for 72 h in complete darkness. Cultures assigned to the SCE assay were treated with 10 µg/ml 5-bromo-2'-deoxyuridine (BrdU) for the entire culture period and colchicine (0.6 µg/ml) for the last 3 h of incubation. In the cultures assigned to CA analysis colchicine at a final concentration of 0.25 µg/ml was present for the entire culture period. According to our previously published results (Lazutka et al., 1999), in such cultures the majority (95–97%) of metaphases were in the first mitotic division after 72 h cultivation. This methodology was recommended and described by Chen and Zhang (1992). The authors showed that colchicine or colcemid added for the entire culture period might be used to obtain pure populations of first division cells. Moreover, in such cultures mitotically arrested first division cells represent lymphocytes with fast and slow proliferation rates and thus a non-random selection of cell populations is avoided. Also, BrdU was not used in such cultures and the possibility that BrdU may enhance induction of spontaneous chromosome damage could be ruled out. The suitability of the method in cytogenetic studies of human populations has been supported by other authors (Scarpato and Migliore, 1996; Lazutka et al., 1999). Cultures were harvested using a routine protocol, including hypotonic treatment with 0.075 M KCl for 20 min at 37°C and three periods of fixation in ethanol:glacial acetic acid (3:1). Flame-dried slides were prepared and stained by the fluorescence plus Giemsa technique (Lazutka, 1996). Such differentially stained slides were used for SCE analysis only. Slides for CA analysis were stained using the conventional Giemsa staining procedure. CAs and SCEs were scored on coded slides using either Zeiss Jenaval or Zeiss Jenamed microscopes at 1250x magnification. Cells were selected for a centromere number not less than 44, good morphology and clear staining. CAs were scored by a single scorer as individual types, but for statistical analysis were grouped as chromatid-type and chromosome-type aberrations. Gaps were not included into the analysis. Detailed scoring criteria were as described previously (Lazutka, 1996). As a rule, no less than 100 first mitotic division cells per individual were analyzed. SCEs were scored by a single scorer in 25–50 second mitotic division cells per individual.
Genotoxicity testing of nitrofurantoin in vitro
Human peripheral blood for in vitro experiments was taken from two healthy adult volunteers. Peripheral blood was added to culture medium prepared as described above. BrdU was present for the entire culture period at a final concentration of 10 µg/ml. Cultures were incubated at 37°C for 72 h. Treatment with nitrofurantoin (OlaineFarm, Latvia) was carried out 48 h after culture initiation and lasted for a period of 24 h. Since the purpose of these studies was to see if cultured lymphocytes are able to reveal possible cytogenetic effects of nitrofurantoin, no external metabolizing systems were added. A working solution of nitrofurantoin was made just before treatment by dissolving it in dimethyl sulfoxide (DMSO) (Merck AG, Germany); the solvent concentration (0.4% v/v) was kept constant in all treated cultures. Two replicates of each treatment were done. Two cultures were left untreated and served as blank controls. Colchicine (0.6 µg/ml) was added 3 h before harvest. Slide preparation and staining were carried out exactly as described above. The slides were coded and scored blind by the same scorer. A total of 100 metaphases per treatment (50 metaphases/replicate) were analyzed for CAs, while 50 metaphases per treatment (25 metaphases/replicate) were analyzed for SCEs. Since good quantitative correspondence between two experiments was found, pooled results are reported in this paper.
Statistical methods
Various statistical methods were used according to the nature of the data and type of analysis needed. Calculations were performed using the InStat and SPSS/PC+ statistical packages. For the analysis of variance, CA data were transformed by the average square root transformation y = 0.5[(x)0.5 + (x + 1)0.5], where x is the level of chromosome damage per 100 cells and y is the transformed variable. SCE data were log transformed before statistical analysis. Both transformations were shown to be very effective in stabilizing the dispersion (Whorton, 1985; Lazutka et al., 1994).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The results of cytogenetic testing of nitrofurantoin in vitro are presented in Table I
. Nitrofurantoin at concentrations of 20 and 40 µM induced chromatid-type aberrations and SCEs in human lymphocytes. No chromosome-type aberrations were induced.
|
No statistically significant increases in CA and SCE frequencies were observed in patients on nitrofurantoin therapy (Tables II and III
). Since CA and SCE frequencies may be affected by factors other than nitrofurantoin, analysis of variance was performed. It showed that CA frequency was not affected by age, previous treatment with antibiotics (mainly ampicillin and/or gentamicin) or therapy with nitrofurantoin. At the same time, the mean frequencies of CAs were higher in the group of children after urethrocystography than in the group of children before the procedure, with significant differences for both chromosome- and chromatid-type aberrations (P < 0.05). A tendency for a slow decrease in urethrocystography-induced CAs with time elapsed since this procedure may be deduced from the data presented in Table II. For eight patients blood samples before treatment and after 1 month of the therapy were available for CA analysis. There were no statistically significant differences in CA frequencies in blood samples before and 1 month after the therapy (3.12 ± 0.99 and 3.88 ± 0.54 CA/100 cells, respectively, P = 0.22, Student's paired t-test).
|
|
Analysis of variance also indicated that SCE frequency was not affected by age, antibiotic treatment, urethrocystography and nitrofurantoin therapy. However, there was a statistically significant correlation (r = 0.6603, P = 0.0270) between cumulative dose of nitrofurantoin and SCE frequency in lymphocytes of children after 1 month of the therapy (Figure 1
). The same tendency was observed in the group of children after 12 months of therapy, although the correlation was not significant due to a smaller sample size (r = 0.5723, P = 0.1794). For 11 patients blood samples before treatment and after 1–12 months of therapy were available. The statistical analysis indicated a significant increase in SCE frequency in blood samples after treatment with nitrofurantoin (6.21 ± 0.28 and 7.30 ± 0.39 SCE/cell, respectively, P = 0.0315, Student's paired t-test).
|
In all cases except two (one with irregular drug usage) prophylaxis with nitrofurantoin was effective: the urinary tract infection did not reappear.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Genotoxicity of nitrofurantoin in vitro was mostly seen in bacteria (Ni et al., 1987
) because the nitro group coupled onto the furan ring was activated by microbial nitroreductases (Hof, 1998). Nitroreductases are present in eukaryotic cells and thus nitrofurantoin may be genotoxic for human cells as well. Our results confirm this presumption, indicating that nitrofurantoin is able to induce SCEs and chromatid-type aberrations in human lymphocytes in vitro. Thus human lymphocytes may be considered as metabolically competent enough to detect the genotoxicity of nitrofurantoin. However, in some previous studies nitrofurantoin failed to induce CAs and SCEs in cultured human lymphocytes (Tonomura and Sasaki, 1973) and normal human fibroblasts (Sasaki et al., 1980), but this was most likely due to inadequate testing, as the highest assayed concentration was 10 µM. Nitrofurantoin was reported to induce CAs in Chinese hamster fibroblast cells at doses of 250–350 µM (Ishidate, 1988), as well as CAs and SCEs in Chinese hamster ovary cells at 20–40 µM (Zeiger et al., 1990). Nitrofurantoin induced SCEs, CAs and micronuclei in rodent bone marrow in vivo (Parodi et al., 1983; Thompson, 1986), but no induction of somatic gene mutations in mouse embryos or chromosome aberrations in secondary spermatocytes were detected (Fonatsch, 1977; Gocke et al., 1983). These discrepancies, however, may be explained by differences between tissues and assay systems. Indeed, recent experiments with other nitrofuran derivatives (7-methoxy-2-nitronaphtho[2,1-b]furan) indicated that very different numbers of mutations were induced in different organs of lacI transgenic mice (Quillardet et al., 2000). The most affected organs belong to the digestive apparatus (small intestine, cecum and colon), while this compound induced practically no mutations in testis and liver of the treated mice.
Despite the clear genotoxicity of nitrofurantoin in human lymphocytes in vitro, the only effect on CAs seen in our in vivo study was a higher frequency of CAs due to the X-ray examination that preceded the nitrofurantoin therapy. Although the effective dose equivalent for urethrocystography was quite low (0.4–2.4 mSv), exposure of radiation workers to similarly low (0.25–3.3 mSv) doses of ionizing radiation has previously been reported to induce a significant increase in acentric fragments as compared with controls (Balasem et al., 1992). We also observed a tendency for a slow decrease in urethrocystography-induced CAs with time elapsed since the procedure. This is in agreement with our previous findings of a time-dependent decrease in chromosome-type aberrations in lymphocytes of another group exposed to low doses of ionizing radiation, the Chernobyl clean-up workers (Lazutka et al., 1999).
A recently published meta-analysis of 10 studies confirms a significant increase in the frequency of micronuclei in peripheral blood lymphocytes after angiography or excretory urography (Norman et al., 2001). Since both procedures use i.v. injections of contrast medium, it was hypothesized that contrast medium enhances, by a photoelectric effect, the X-ray dose absorbed by the lymphocytes. In our case, however, contrast medium was introduced directly into the urinary tract, thus its concentration in the blood should not be high enough for dose enhancement. Consequently, the increased frequency of CAs observed in lymphocytes of children after urethrocystography cannot be attributed to the action of contrast medium.
As mentioned above, the only earlier study on the genotoxicity of nitrofurantoin in human cells in vivo was performed with 15 adult UTI patients treated with daily oral doses of 10 mg/kg for 10 days (Sardays et al., 1990). No increase in SCE frequency was reported. Daily nitrofurantoin doses in our study were lower (1–2 mg/kg), but the treatment duration was much longer (up to 12 months). Moreover, the half-life of nitrofurantoin in children is about twice as long compared with adults (Wierzba et al., 1982). Thus, total exposure doses in our study may be considered quite high. In spite of this, no increase in CA frequency was observed in lymphocytes of children treated with nitrofurantoin. The results of the SCE analysis may be considered as suggesting further studies. On the one hand, no increase in SCE frequency was seen in groups of children treated with nitrofurantoin for 1 and 12 months; the 3 and 6 month sample sizes were too small for adequate conclusions. On the other hand, for those patients whose blood samples were available both before and after treatment with nitrofurantoin, a statistically significant increase in SCE rates was detected. A statistically significant correlation between cumulative dose of nitrofurantoin and SCE frequency in lymphocytes of children after 1 month of the therapy also indicated that the increase was not due to chance. At the same time, this correlation cannot be explained in terms of a simple dose–response relationship, because the treatment dose was almost the same for all patients. The increase in SCE frequency was small, but nitrofurantoin was not a very effective SCE inducer in vitro either. In addition, individual variations in SCE frequency may have partly concealed the effect in the total group.
CAs in lymphocytes are often considered a good biomarker of human cancer risk (Bonassi et al., 2000). Thus our negative results with CAs in vivo are generally in line with some detailed carcinogenicity studies with rodents indicating that nitrofurantoin does not induce a treatment-related increase in the incidence of neoplasms at any site (Stitzel et al., 1989; Butler et al., 1990; Hasegawa et al., 1990). However, positive findings with CAs and SCEs in vitro and the suggestive effect of nitrofurantoin therapy on SCEs in vivo indicate that further, much larger follow-up studies are needed to elucidate the genetic safety of therapeutic use of nitrofurantoin.
|
Notes |
|---|
2 To whom correspondence should be addressed. Tel: +370 2 332864; Fax: +370 2 330068; Email: grazina.slapsyte{at}gf.vu.lt
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
-
Balasem,A.N., Ali,A.-S.K., Mosa,H.S. and Hussain,K.O. (1992) Chromosomal aberration analysis in peripheral lymphocytes of radiation workers. Mutat. Res., 271, 209–211.[Medline]
Bollgren,J. (1999) Antibacterial prophylaxis in children with urinary tract infection. Acta Paediatr., 88 (suppl.), 48–52.[Web of Science][Medline]
Bonassi,S., Hagmar,L., Stromberg,U., Montagud,A.H., Tinnerberg,H., Forni,A., Heikkilä,P., Wanders,S., Wilhardt,P., Hansteen,I.L., Knudsen,L.E. and Norppa,H., for the European Study Group on Cytogenetic Biomarkers and Health (2000) Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer. Res., 60, 1619–1625.
Butler,W.H., Graham,T.C. and Sutton,M.L. (1990) Chronic toxicity and oncogenicity studies of Macrodantin in Sprague–Dawley rats. Food Chem. Toxicol., 28, 269–277.[Web of Science][Medline]
Chen,D.-q. and Zhang,C.-y. (1992) A simple and convenient method for gaining pure populations of lymphocytes at the first mitotic division in vitro. Mutat. Res., 282, 227–229.[Medline]
Fonatsch,C. (1977) Effect of nitrofurantoin on meiosis of the male mouse. Hum. Genet., 39, 345–351.[Medline]
Gocke,E., Wild,D., Eckhardt,K. and King,M.T. (1983) Mutagenicity studies with the mouse spot test. Mutat. Res., 117, 201–212.[Web of Science][Medline]
Hasegawa,R., Murasaki,G., St John,M.K., Zenser,T.V. and Cohen,S.M. (1990) Evaluation of nitrofurantoin on the two stages of urinary bladder carcinogenesis in the rat. Toxicology, 62, 333–347.[Medline]
Hof,H. (1998) Antimicrobial therapy with nitroheterocyclic compounds, for example, metronidazole and nitrofurantoin. Immun. Infekt., 16, 220–225 (in German).
Ishidate,M.Jr (1988) Data Book on Chromosomal Aberration Test In Vitro. Elsevier, Amsterdam, The Netherlands.
Lazutka,J.R. (1996) Chromosome aberrations and rogue cells in lymphocytes of Chernobyl clean-up workers. Mutat. Res., 350, 315–329.[Web of Science][Medline]
Lazutka,J.R., Dedonyt,V. and Krapavickait,D. (1994) Sister-chromatid exchanges and their distribution in human lymphocytes in relation to age, sex and smoking. Mutat. Res., 306, 173–180.[Web of Science][Medline]
Lazutka,J.R., Lekevie
ius,R., Dedonyt,V., Maciulevii
t-Gervers,L., Mierauskien,J., Rudaitien,S. and Slapyt,G. (1999) Chromosome aberrations and sister-chromatid exchanges in Lithuanian population: effects of occupational and environmental exposures. Mutat. Res., 445, 225–239.[Web of Science][Medline]
Norman,A., Cochran,S.T. and Sayre,J.W. (2001) Meta-analysis of increases in micronuclei in peripheral blood lymphocytes after angiography or excretory urography. Radiat. Res., 155, 740–743.[Web of Science][Medline]
Ni,Y.C., Heflich,R.H., Kadlubar,F.F. and Fu,P.P. (1987) Mutagenicity of nitrofurans in Salmonella typhimurium TA98, TA98NR and TA98/1,8-DNP6. Mutat. Res., 192, 15–22.[Web of Science][Medline]
Parodi,S., Pala,M., Russo,P., Balbi,C., Abelmoschi,M.L., Taninger,M., Zunino,A., Ottaggio,L., de Ferrari,M., Carbone,A.and Santi,L. (1983) Alkaline DNA fragmentation, DNA disentanglement evaluated viscosimetrically and sister chromatid exchanges, after treatment in vivo with nitrofurantoin. Chem. Biol. Interact., 45, 77–94.[Web of Science][Medline]
Quillardet,P., Michel,V., Arrault,X., Hofnung,M. and Touati,E. (2000) Mutagenic properties of a nitrofuran, 7-methoxy-2-nitronaphtho[2,1-b]furan (R7000), in lacI transgenic mice. Mutat. Res., 470, 177–188.[Web of Science][Medline]
Sasaki,M., Sugimura,K., Yoshida,M.A. and Abe,S. (1980) Cytogenetic effects of 60 chemicals on cultured human and chinese hamster cells. La Kromosomo, 20, 574–584.
Sardays,S., Metin,A., Gyok,S., Karakaya,A.E. and Aykol,N. (1990) Sister chromatid exchanges in peripheral lymphocytes of urinary tract infection patients treated with nitrofurantoin. Int. Urol. Nephrol., 22, 513–517.[Medline]
Scarpato,R. and Migliore,L. (1996) Comparison of spontaneous structural chromosome aberration frequency in 48 h-cultured human lymphocytes mitotically arrested by different colcemid treatments. Mutat. Res., 361, 35–39.[Medline]
Steineck,G., Wiholm,B.E. and Gerhardsson de Verdier,M. (1995) Acetaminophen, some other drugs, some diseases and the risk of transitional cell carcinoma. A population-based case-control study. Acta Oncol., 34, 741–748.[Web of Science][Medline]
Stitzel,K.A., McConnell,R.F. and Dierckman,T.A. (1989) Effects of nitrofurantoin on the primary and secondary reproductive organs of female B6C3F1 mice. Toxicol. Pathol., 17, 774–781.[Medline]
Thompson,E.D. (1986) Comparison of in vivo and in vitro cytogenetic assay results. Environ. Mutagen., 8, 753–767.[Medline]
Tonomura,A. and Sasaki,M.S. (1973) Chromosome aberrations and DNA repair synthesis in cultured human cells exposed to nitrofurans. Jpn. J. Genet., 48, 291–294.
Uhari,M., Nuutinen,M. and Turtinen,J. (1996) Adverse reactions in children during long-term antimicrobial therapy. Pediatr. Infect. Dis. J., 15, 404–408.[Web of Science][Medline]
Whorton,E.B. (1985) Some experimental design and analysis considerations for cytogenetic studies. Environ. Mutagen., 7, 9–15.
Wierzba,K., Wankowicz,B., Rogoyski,A., Prokopczyk,J., Piekarczyk,A., Kaminska,E. and Bozkov,K. (1982) Experimental and clinical pharmacokinetics of nitrofurantoin in the early period of life. Paediatr. Paedol., 17, 293–299.
Zeiger,E., Haseman,J.K., Shelby,M.D., Margolin,B.H. and Tennant,R.W. (1990) Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals. Environ. Mol. Mutagen., 16, 1–14.[Web of Science][Medline]
Zhanel,G.G., Karlowsky,J.A., Harding,G.K., Carrie,A., Mazzulli,T., Low,D.E. and Hoban,D.J. (2000) A Canadian national surveillance study of urinary tract isolates from outpatients: comparison of the activities of trimethoprim-sulfametoxazole, ampicillin, mecillinam, nitrofurantoin and ciprofloxacin. Antimicrob. Agents Chemother., 44, 1089–1092.
Received on August 14, 2000; accepted on August 13, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Quillardet, X. Arrault, V. Michel, and E. Touati Organ-targeted mutagenicity of nitrofurantoin in Big Blue transgenic mice Mutagenesis, September 1, 2006; 21(5): 305 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. I. Gonzalez Borroto, G. Perez Machado, A. Creus, and R. Marcos Comparative genotoxic evaluation of 2-furylethylenes and 5-nitrofurans by using the comet assay in TK6 cells Mutagenesis, May 1, 2005; 20(3): 193 - 197. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||