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PubMed1998

Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane-water.

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had not been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent thermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was measured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibration with the solvent mixture. The thermal properties of the solid phases did not show significant changes. The three drugs display a solubility maximum against the cosolvent ratio. The solubility peaks of acetanilide and nalidixic acid shift to a more polar region at the higher temperatures. Nonlinear van't Hoff plots were observed for nalidixic acid whereas acetanilide and paracetamol show linear behavior at the temperature range studied. The apparent enthalpies of solution are endothermic going through a maximum at 50% dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Solubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The enthalpy-entropy compensation analysis also suggests that two different mechanisms, dependent on cosolvent ratio, are involved in the solubility enhancement of the three drugs. The plots of deltaH versus deltaG are nonlinear, and the slope changes from positive to negative above 50% dioxane. The compensation effect for the thermodynamic magnitudes of transfer from water to the aqueous mixtures can be described by a common empirical nonlinear relationship, with the exception of paracetamol, which follows a separate linear relationship at dioxane ratios above 50%. The results corroborate earlier findings with phenacetin. The similar pattern shown by the drugs studied suggests that the nonlinear enthalpy-entropy compensation effect may be characteristic of the solubility of semipolar drugs in dioxane-water mixtures.

Acetaminophen↗

PubMed2004

Azithromycin as an alternative to nalidixic acid in the therapy of childhood shigellosis.

In an outbreak of shigellosis in a kibbutz in Northeastern Israel, oral nalidixic acid failed clinically in 35% and microbiologically in 28.4% of 14 children as compared with no clinical and microbiologic failure in 25 children who were treated with oral azithromycin (P < 0.01 and 0.012, respectively). Thus azithromycin could be a suitable alternative to nalidixic acid.

Administration, Oral↗

PubMed1983

Recombinogenic activity of nalidixic acid for artificial hybrids but not for natural strains of Candida albicans: evidence for the monoploidy of natural strains.

Nalidixic acid induces segregation of auxotrophs from prototrophic hybrids of Candida albicans artifically produced by fusing complementing auxotrophic protoplasts. The auxotrophies recovered are limited to those introduced through the fusion process, and patterns of segregations for linked auxotrophic markers demonstrate the segregants are products mitotic crossing-over. Nalidixic acid does not induce auxotrophies of any sort in clinical isolates of C. albicans. These findings are contrary to a current hypothesis that natural strains of C. albicans are diploid and heterozygous for a variety of auxotrophic mutations.

Adenine↗

PubMed1984

The in-vitro activity of ciprofloxacin compared with that of norfloxacin and nalidixic acid.

The in-vitro activity of ciprofloxacin , a new 4-quinolone, was compared with that of norfloxacin and nalidixic acid against recent clinical isolates of medically important bacteria. Overall, ciprofloxacin and norfloxacin had similar spectra of activity, but ciprofloxacin had somewhat greater intrinsic activity against most organisms. Minimum inhibitory concentrations (MIC) were in the range 0.004-4 mg/l for Enterobacteriaceae, 0.016-2 mg/l for Pseudomonas spp., 0.004-1 mg/l for Acinetobacter, 0.004-0.016 mg/l for Haemophilus influenzae, 0.001-0.004 for gonococci, 0.004-0.03 mg/l for Cmpylobacter , 0.12-2 mg/l for staphylococci, 0.25-4 mg/l for streptococci, 1-32 mg/l for the Bacteroides fragilis group and mostly in the range 0.25-8 mg/l for other obligate anaerobes. Resistant variants could be selected readily in vitro by culture on any of the three compounds investigated. However, while the MICs of nalidixic acid were high for these variants those of ciprofloxacin and norfloxacin were much lower.

Anti-Bacterial Agents↗

PubMed1979

The effect of nalidixic acid on microaerophilic and anaerobic bacteria. Special study of clostridia.

Study of the sensitivity of 141 strains of anaerobic and microaerophilic bacteria to nalidixic acid shows that few bacteria are inhibited by low concentrations (Veillonella, Eikenella, most of the Clostridia). Nalidixic acid appears to be bactericidal with respect to Clostridium perfringens, and its point of attack in the DNA is probably different from that of metronidazole.

Anaerobiosis↗

PubMed1980

[Resistance of the ocular conjunctival tissues to nalidixic acid in rabbits (author's transl)].

Microscopic examination of the articular cartilage of adult and young rabbits after daily intraperitoneal injections of 0.50 g/kg of nalidixic acid for four weeks demonstrated the presence of characteristic lesions due to nalidixic acid in the young animals only. No modification of the texture of the cornea or sclera was noted after microscopic examination of either young or adult animals, and no alterations were present in the juxtascleral cartilage.

Animals↗

PubMed1986

Nalidixic acid and trimethoprim/sulphamethoxazole as alternatives for short-term treatment of urinary infections.

The efficacy of 3-day therapy with nalidixic acid in 16 children, and trimethoprim/sulphamethoxazole in 19 children, was studied prospectively in children with an acute infection of the lower urinary tract and compared with that of a conventional 10-day course with the same drugs. The immediate cure rate was 97% in the 3-day group and 90% in the 10-day group. During 3 months of follow-up there were altogether six re-infections in children given short-term treatment and six in the conventionally treated group. The results give further support for the suggestion that 3-day therapy is equivalent to 10-day treatment in uncomplicated urinary infections in children and that both nalidixic acid and trimethoprim/sulphamethoxazole are good alternatives in such an approach.

Adolescent↗

PubMed1982

Pharmacokinetics of nalidixic acid in old and young volunteers.

Plasma levels of active naphthyridine were measured in healthy old (mean age 77.3 years) and young (mean age 25.4 years) subjects following oral administration of 1 Gm nalidixic acid. The plasma levels of active naphthyridine, i.e., nalidixic acid and its metabolite 7-hydroxynalidixic acid, were generally higher in the old group, particularly in the elimination phase. Significant variations in the pharmacokinetic parameters were obtained between the two groups of volunteers. The plasma half-life of active naphthyridine averaged 11.5 hours in old subjects and 2.7 hours in the younger group. Diminished renal function in the geriatric group may explain the slower elimination of the drug in the old subjects. The mean values of the other parameters calculated were: apparent volume of distribution, 0.55 (old) and 0.47 (young) liter/kg body weight; area under the curve, 327.7 (old) and 156.3 (young) micrograms/ml x hr; total body clearance 2.9 (old) and 8.3 (young) liters/hr; absorption rate constant, 0.29 (old) and 0.52 (young) hr. -1

Adult↗

PubMed1973

Effect of nalidixic acid on PBS2 bacteriophage infection of Bacillus subtilis.

Infection of Bacillus subtilis by PBS2 phage, whose DNA contains uracil instead of thymine, is relatively unaffected by low concentrations of nalidixic acid which severely inhibit B. subtilis DNA synthesis. High concentrations of nalidixic acid do inhibit PBS2 DNA synthesis, but more severely reduce the burst size of PBS2 infections. Hydroxyurea blocks PBS2 DNA synthesis, preventing progeny phage production.

Bacillus subtilis↗

PubMed1989

Genetic profile of a nalidixic acid analog: a model for the mechanism of sister chromatid exchange induction.

In recent years, evidence has accumulated that suggests that mammalian topoisomerase may play a role in the formation of spontaneous or chemically induced sister chromatid exchange (SCE). In microbial systems, nalidixic acid is known to disrupt the function of a topoisomerase-like enzyme, DNA gyrase. To explore the possible relationship to topoisomerase function and SCE formation in mammalian cells, an analog of nalidixic acid with potent topoisomerase II inhibitory activity was selected for examination in a variety of genetic toxicology assays. This analog, CP-67,015, proved to be a positive direct-acting mutagen in the L5178Y/TK+/-, CHO/HGPRT, and V79/HGPRT systems. However, no gene mutational activity was observed using the Ames test in direct plate, mouse and rat metabolic activation, and mouse urine tests. In vitro cytogenetic studies showed strong clastogenic activity in human lymphocytes and in CHO cells. Compound-induced chromosome damage was also observed in vivo in mouse bone marrow cells. Surprisingly, SCE studies in vitro in human lymphocytes or CHO cells showed only slight increases, even at levels producing severe chromosome breakage. Mouse bone marrow showed no significant elevation of SCE following parenteral treatment with CP-67,015. These results, taken together, demonstrate that CP-67,015 is a direct-acting mutagen in mammalian cells with both gene and chromosomal level effects. The relative ineffectiveness in producing SCEs suggests that CP-67,015 may interfere with a DNA replicative/repair process, perhaps by alteration of one or more DNA polymerase activities. This suggestion is based in part on the known effect of the analog nalidixic acid on DNA gyrase in microbial cells and on topoisomerase in mammalian cells. The profile of genetic activity of CP-67,015, coupled with its inhibitory effect on topoisomerase function, gives rise to a model for SCE formation that is based on anomalies of topoisomerase activity during DNA synthesis.

4-Quinolones↗

PubMed2003

Determination of ciprofloxacin and nalidixic acid resistance in Campylobacter jejuni with a fluorogenic polymerase chain reaction assay.

A fluorogenic polymerase chain reaction assay for the gyrA gene was used to determine the frequency of a Thr-86 mutation in Campylobacter jejuni isolates from food animals and humans in northern Thailand and to investigate the correlation between this mutation and bacterial resistance to fluoroquinolones. Eighty-four isolates of C. jejuni were used: 65 from healthy chickens on farms, 16 from chickens at the slaughterhouse, 1 from chicken meat at the market, and 1 from a healthy farm worker. The microbroth dilution technique was used for in vitro susceptibility testing. MIC breakpoints established by the National Antimicrobial Resistance Monitoring System were used to categorize the resistance of C. jejuni to ciprofloxacin and nalidixic acid. Sixty of the 84 C. jejuni isolates tested carried the Thr-86 mutation in the gyrA gene. All isolates with ciprofloxacin MICs of > or = 2 mg/liter carried the mutation, and no isolates with nalidixic acid MICs of < or = 16 mg/liter carried the Thr-86-to-Ile mutation. There was a very strong association between ciprofloxacin resistance and the presence of the mutation (kappa = 0.971, P < 0.01). The association between the presence of the Thr-86-to-Ile mutation and nalidixic acid resistance was weaker (kappa 0.859: P < or = 0.01).

Abattoirs↗

PubMed1973

Nalidixic acid susceptibility testing of clinical isolates of Serratia marcescens.

Nalidixic acid (nal) susceptibility of clinical isolates of Serratia marcescens from urinary tract infections, wounds, and blood was determined by the standard disk method, and results were compared with results obtained by a standardized tube dilution procedure using five different broth media. An attempt was made to approximate in vivo conditions by using urine as a test medium and correlating the activity of nal in urine with its activity in nutrient, Trypticase soy, brain-heart infusion, and Mueller-Hinton broths. The isolates were consistently susceptible to lower concentrations of nal in nutrient broth than in the other media. The results showed that Mueller-Hinton broth most closely reflected nal activity in urine. A standardized procedure for nal susceptibility testing of urinary tract isolates of S. marcescens is proposed.

Anti-Bacterial Agents↗

PubMed1979

Population changes induced in Candida albicans by nalidixic acid.

Cells of Candida albicans plated on media containing nalidixic acid (Nal) either die, adapt physiologically to Nal-tolerance or mutate ot Nal-resistance. The fraction of a population exhibiting each response depends on the growth phase of cells when plated and their nitrogen and carbon nutrition and growth temperatures before and after plating. Nal induces Nal-resistant mutants in very high frequency but only at 37 C on plates containing i) glucose as primary carbon source and ii) adenine, a sulfur amino acid or a representative of the glutamic acid family of amino acids. Nal does not affect either forward mutation to caffeine-resistance or reverse mutation from histidine auxotrophy to prototrophy. Nal-resistant mutants produce minute colonies on N-ALfree medium, respire oxidatively and are unusually sensitive to inhibitors of oxidative phosphorylation. They revert spontaneously to wild type at very high rates but can be propagated indefinitely in the absence of Nal by serial selection and replating of minute colonies. Cellular inactivation and induction of Nal-resistant mutants are greatly affected by specific inhibitors of mitochondrial macromolecular syntheses. The presence of chloramphenicol or erythromycin during exposure to Nal prevents cell death and mutation but has no effect on adaptation to Nal-tolerance. Growth on acriflavin or ethidium bromide enhances resistance of cells to inactivation when subsequently plated on Nal containing media. It is concluded that Nal-induced cellular inactivation and mutation to Nal-resistance, but not adaptation to Nal-tolerance, result from damages to the mitochondrion which are fixed or promoted by macromolecular syntheses within the mitochondrion. Implications of these findings for the therapeutic use of Nal are discussed.

Azides↗

PubMedDate not supplied

Liquid chromatographic determination of nalidixic acid in pharmaceutical preparations.

A simple, rapid, and environmentally safe liquid chromatographic (LC) method was developed for the qualitative and quantitative determination of pharmaceutical preparations of nalidixic acid. The new method was applied to commercial preparations of tablets and a suspension of nalidixic acid and found to be satisfactory for both quantitative and qualitative determinations. Previous LC methods either used chloroform to extract, which we were trying to eliminate, or used a mobile phase of about pH 2.5, which will destroy the column coating. The LC system for the new method uses sulfanilic acid as internal standard, a mu-Bondapak C18 column, and a mobile phase of methanol, 0.0045M dibasic potassium phosphate, and 0.0072M hexadecyltrimethylammonium bromide. The detection wavelength is 254 nm. The sample is dissolved in methanol, and an aliquot is injected through a 20 microL injection loop. Average recoveries ranged from 99.4 to 101.3%.

Anti-Infective Agents↗

PubMed1994

Growth and joint symptoms in children treated with nalidixic acid.

To analyze the effects of quinolones on growth and joints in children we identified 78 patients who had been receiving nalidixic acid for 116 days on the average (range, 3 to 570 days) from a random sample of 3094 of 16,409 children treated with long term medication because of recurrent urinary tract infection. Two controls per each index case, matched for sex and the age at which the first medication for recurrent urinary tract infection occurred, were chosen. Frequency of joint symptoms and examinations or possible treatments for arthropathies were similar in the index (n = 44) and control (n = 62) cases. Detailed growth data were analyzed from 39 case-control pairs after the mean follow-up time of 19.6 years (range, 14.8 to 24.7 years), and no growth disturbances were found. The final heights (age, > 18 years) of the index and control cases were similar (n = 31 case-control pairs). We conclude that nalidixic acid does not cause arthropathies or hamper growth in children, which supports the suggestion that at least short treatment periods with quinolones are safe.

Adolescent↗

PubMed1992

[Effect of ofloxacin, ciprofloxacin and nalidixic acid on serum theophylline level in patients treated with methylxanthine preparations].

The effect of two new quinolones, ofloxacin and ciprofloxacin and nalidixic acid on serum theophylline level in 17 asthma patients treated with methylxanthines was evaluated. Each quinolone was administered one tablet twice daily to all patients for three days. Blood samples were taken before quinolone administration and 1 h, 3h and 5 h after taking the drug on the first day. Last sample was taken 5 h after quinolone administration on the third day of therapy. The serum theophylline concentration was determined by 3 M Theo FAST test. It was found that in the patients treated with ciprofloxacin serum theophylline level in all samples was significantly higher as compared with the control sample. In the patients receiving ofloxacin the theophylline level only 1 h after receiving the drug the increase was statistical significant. Nalidixic acid had no influence on serum theophylline concentration. As these studies show, the new quinolones should be applied with great caution in patients treated with high doses of methylxanthines or in patients with decreased methylxanthines clearance. In patients with chronic obturative diseases and pulmonary infections the safer drug would appear to be ofloxacin.

Administration, Oral↗

PubMed1988

Severe anaphylactoid reaction to nalidixic acid.

We present the case of a 58-year-old non-atopic woman who suffered an adverse reaction to orally administered nalidixic acid, which had been prescribed for the treatment of a urinary tract infection. The single-blind oral provocation test was positive; the patient presented the clinical features of an anaphylactoid reaction 3 min after administration of nalidixic acid. Both the skin test and the histamine release test were negative. These results suggest that we are dealing with an anaphylactoid reaction not described before with this drug.

Anaphylaxis↗

PubMed1977

Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity.

ATP-dependent DNA supercoiling catalyzed by Escherichia coli DNA gyrase was inhibited by oxolinic acid, a compound similar to but more potent than nalidixic acid and a known inhibitor of DNA replication in E. coli. The supercoiling activity of DNA gyrase purified from nalidixic acid-resistant mutant (nalA(R)) bacteria was resistant to oxolinic acid. Thus, the nalA locus is responsible for a second component needed for DNA gyrase activity in addition to the component determined by the previously described locus for resistance to novobiocin and coumermycin (cou). Supercoiling of lambda DNA in E. coli cells was likewise inhibited by oxolinic acid, but was resistant in the nalA(R) mutant. The inhibition by oxolinic acid of colicin E1 plasmid DNA synthesis in a cell-free system was largely relieved by adding resistant DNA gyrase. In the absence of ATP, DNA gyrase preparations relaxed supercoiled DNA; this activity was also inhibited by oxolinic acid, but not by novobiocin. It appears that the oxolinic acid-sensitive component of DNA gyrase is involved in the nicking-closing activity required in the supercoiling reaction. In the presence of oxolinic acid, DNA gyrase forms a complex with DNA, which can be activated by later treatment with sodium dodecyl sulfate and a protease to produce double-strand breaks in the DNA. This process has some similarities to the known properties of relaxation complexes.

DNA, Bacterial↗