Studies on cinoxacin. 1. In vitro activity of cinoxacin, as compared to nalidixic acid, against urinary tract pathogens.
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Anti-Infective Agents, Urinary↗
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Studies on cinoxacin. 2. Assay of cinoxacin in body fluids and tissues.
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Anti-Infective Agents, Urinary↗
Studies on cinoxacin. 3. Concentrations of cinoxacin in serum, urine and tissues of urological patients.
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Adult↗
Influence of urinary pH on the pharmacokinetics of cinoxacin in humans and on antibacterial activity in vitro.
The impact of acidification and alkalinization of the urine on the pharmacokinetics of cinoxacin was examined after single 500-mg oral doses were administered to nine healthy male volunteers. Acidic and alkaline conditions were achieved by repeated oral doses of ammonium chloride or sodium bicarbonate, respectively. Plasma cinoxacin levels in all subjects were adequately described in terms of one-compartment-model kinetics with first-order absorption and elimination. Acidification and alkalinization treatment had no effect on cinoxacin absorption or distribution. The mean elimination half-life of cinoxacin in plasma was 1.1, 2.0, and 0.6 h in control subjects and with acidification and alkalinization of urine, respectively. Recovery of intact cinoxacin in samples of urine collected 0 to 36 h after cinoxacin administration represented 65% of the dose in control subjects and urine acidification and 80% of the dose with alkalinization of urine. The mean renal clearance of cinoxacin was 76, 118, and 278 ml/min with acidification, control, and alkalinization, respectively, and renal clearance was highly correlated with urinary pH. Urine concentrations of cinoxacin were significantly higher with alkalinization compared with control values during the first 4 h after drug administration. Urine cinoxacin concentrations were reduced somewhat by acidification, but these tended not to be significantly different from control values. Changes in cinoxacin elimination owing to urine pH are less pronounced in humans than in dogs. The antibacterial activity of cinoxacin against some common urinary tract pathogens was pH dependent. A four- to eightfold reduction in cinoxacin activity was generally observed at pH 8 compared with lower pH values. However, in view of the high levels of cinoxacin which are obtained in both acidic and basic urine, the impact of urine pH on cinoxacin antibacterial efficacy would be of minor clinical importance.
Adult↗
Time-dependent elimination of cinoxacin in rats.
The effect of the variation of urinary pH on the pharmacokinetics of the acidic antibacterial agent, cinoxacin (pKa 4.60), was examined. Urinary pH of 24-h fasted rats remained at about pH 6 during the daytime, while that of nonfasted rats was high (about pH 7.5) in the morning and gradually decreased to a pH similar to that of the fasted rat in the afternoon. The free fraction of cinoxacin in fasted rat sera in the morning was similar to that in nonfasted rats despite the longer half-life of cinoxacin in fasted rats. In the afternoon the free fraction was slightly different despite similar cinoxacin elimination in fasted and nonfasted rats. These findings seemed to exclude the contribution of protein binding from the causes of increased cinoxacin elimination in nonfasted rats in the morning. Elimination rate constants of cinoxacin obtained with a one-compartment open model correlated well with urinary pH 30 min after injection, suggesting that the urinary pH plays a more important role in cinoxacin elimination. When cinoxacin was orally administered to fasted rats at 11:00, the area under the plasma concentration-time curve was threefold larger than in nonfasted rats. As found with the intravenous administration, this difference may be explained by the prolonged half-life caused by decreased urinary pH after fasting. This study revealed the time-dependent elimination of cinoxacin in nonfasted rats, which is related to physiological change of urinary pH caused by food intake.
Animals↗
Cinoxacin: competitive inhibitory effect on p-aminohippurate transport and its uptake in renal cortical slices.
The effect of cinoxacin on p-aminohippurate (PAH) transport and the accumulation of cinoxacin were examined in renal cortical slices. Cinoxacin significantly inhibited the uptake of PAH by the slices from rats and rabbits. Cinoxacin increased the apparent Michaelis constant (Km) but did not affect Vmax for PAH uptake by rat kidney cortical slices, suggesting that cinoxacin inhibited PAH transport in a competitive manner. Cinoxacin was taken up but did not affect the cellular metabolism of Na+, K+ and ATP in the slices from rats and rabbits, except that 740 microM cinoxacin increased net Na+ efflux. These data indicate that cinoxacin is transported by the same process as that of PAH in renal cortical slices. Lastly, repeated administration of cinoxacin to rats did not affect the uptake of the drug by the slices.
Adenosine Triphosphate↗
Influence of probenecid on serum levels and urinary excretion of cinoxacin.
Serum levels and urinary excretion of cinoxacin were examined in healthy individuals after a two-step intravenous infusion in the presence and absence of probenecid. After dosing cinoxacin alone, steady-state serum levels were approached in 1 h and were maintained for an additional 2 h with a reduced infusion rate. After probenecid pretreatment, serum levels of cinoxacin continued to increase during 3 h of infusion, reaching levels approximately double those obtained with cinoxacin alone. The mean elimination half-life of cinoxacin from serum was increased from 1.3 to 3.5 h in the presence of probenecid, and renal clearance was significantly reduced, with 46% of dosed drug appearing in 7-h urines of probenecid-treated subjects compared with 68% in subjects receiving cinoxacin alone. Probenecid had no apparent influence on cinoxacin distribution in the body but caused a significant decrease in the rate of cinoxacin extrarenal elimination, possibly due to competition for a common metabolic pathway.
Adult↗
Cinoxacin (Cinobac, Eli Lilly & Co.).
Cinoxacin, a synthetic organic acid antibacterial agent, related structurally to nalidixic and oxolinic acid, has been approved for the treatment of initial and recurrent urinary tract infections (UTIs) caused by susceptible gram-negative microorganisms. The role of cinoxacin in the treatment of UTIs, compared with the usual first-line agents, is uncertain at this time. The efficacy of cinoxacin in the treatment of pyelonephritis, compared with these proven agents, has been examined in only small numbers of patients, and cinoxacin is more expensive than these agents. Cinoxacin may prove valuable in the treatment of prostatitis and in the prophylaxis of recurrent UTIs; further study in these areas is warranted. In the routine treatment of acute UTIs, cinoxacin perhaps should be reserved only for those patients with organisms resistant to usual first-line agents or those who fail to respond to therapy with these agents. In this respect, cinoxacin may, in the future, replace nalidixic acid.
Cinoxacin↗
Cinoxacin complexes with divalent metal ions. Spectroscopic characterization. Crystal structure of a new dinuclear Cd(II) complex having two chelate-bridging carboxylate groups. Antibacterial studies.
Several cinoxacin (HCx) complexes with divalent metal ions have been prepared and characterized by spectroscopic techniques. The crystal structure of [Cd2(Cx)4(H2O)2].10H2O has been determined by X-ray diffraction. The complex is triclinic, space group P1 with unit-cell dimensions: a = 10.412(2), b = 11.119(2), c = 13.143(6)A, chi== 76.78(4) degrees, beta = 74.59(3) degrees, gamma = 77.12(3) degrees, V = 1406.0(8) A3. In this complex each cadmium atom is heptacoordinated: the metal environment is formed by two Oketo and two Ocarbox atoms from two different cinoxacinate monoanions, two carboxylate oxygen atoms from a third cinoxacinate ligand and by one water oxygen atom on the seventh position. Two of the cinoxacinate ions act as tridentate chelate and bridging ligands and the other one as a bidentate chelate ligand. In the bridging monoanions the carboxylate group is behaving as a chelate ligand. All the complexes were screened for their activity against several bacteria, showing activity similar to that of cinoxacin. Additionally, the number of bacteria killed after 3 h of incubation with cinoxacin, [Cu(Cx)2].2H2O and [Co(Cx)3]Na.10H2O complexes was determined against E. coli ATCC 25922; the copper compound presents paradoxical effect which has been described and related to the mechanism of action of quinolones.
4-Quinolones↗
Comparison of low-dose cinoxacin therapy and placebo in the prevention of recurrent urinary tract infections.
Fifty-nine female patients with a history of at least three episodes of urinary tract infection in the preceding year were enrolled in a two-center, double-blind study comparing cinoxacin and placebo as preventive therapy. Evaluation of efficacy was based on the results from 41 patients for whom complete data were available. In the cinoxacin-treated group, 18 of 20 patients remained asymptomatic during the study, compared with 11 of 21 patients in the placebo group. This difference between the two treatment groups was significant (P = 0.031). One patient in the cinoxacin group and eight patients in the placebo group developed an infection during the study. This difference was also significant (P = 0.045). Nine patients spontaneously reported adverse reactions, four in the cinoxacin group and five in the placebo group. In four instances, these were sufficiently severe for the treatment to be withdrawn from one patient who received cinoxacin and three patients who received placebo. The results of this study have shown that cinoxacin was significantly more effective than placebo in preventing urinary tract infection in patients with a history of frequent recurrent infections.
Adult↗
A comparison of cinoxacin and co-trimoxazole in the treatment of cystitis.
This paper describes a study of patients with cystitis treated with 1 gm/day of cinoxacin or four tablets/day of co-trimoxazole (trimethoprim, 80 mg, and sulfamethoxazole, 400 mg), both drugs given twice a day for 14 days. Of the 64 patients with cystitis, complete bacteriological data were available for 27 patients in the cinoxacin group and 23 patients in the co-trimoxazole group. In most instances, the infecting organism was Escherichia coli. Twenty-six (96%) patients who received cinoxacin and 22 (96%) patients who received co-trimoxazole had a satisfactory clinical response. Two patients on cinoxacin became reinfected with a new pathogen, and one had a recurrence of infection with the same pathogen; on patient on co-trimoxazole became reinfected with a new pathogen. Adverse reactions were reported by six (19%) of the 32 patients in the cinoxacin group, none of whom discontinued therapy, and by 18 (56%) of the 32 patients in the co-trimoxazole group, five of whom withdrew from the study. These differences between the groups were significant (P less than 0.05). It is concluded that cinoxacin is an effective, well-tolerated agent for use in cystitis caused by the common pathogens.
Adult↗
Cinoxacin: in vitro antibacterial studies of a new synthetic organic acid.
Cinoxacin (compound 64716) is a synthetic organic acid with antibacterial activity against most aerobic gram-negative bacilli. Minimal inhibitory concentrations of cinoxacin (agar-dilution method) were determined for 419 strains. Escherichia coli was the most susceptible group of organisms. The majority of Klebsiella sp., Enterobacter sp., Proteus sp., and Serratia marcescens were inhibited by 8 mug of cinoxacin per ml. Pseudomonas aeruginosa and all gram-positive isolates tested were resistant to 64 mug or less of cinoxacin per ml. Zones of inhibition using a 30-mug disk correlated well with agar-dilution minimal inhibitory concentrations (r = -0.9). Cinoxacin was bactericidal when tested with inocula of 5 x 10(6) organisms per ml. Resistance to cinoxacin was readily developed in all three strains tested by serial passage on drug-containing agar. The in vitro properties of this agent were similar to those of nalidixic acid.
Anti-Bacterial Agents↗
Effect of cinoxacin on cellular metabolism and p-aminohippurate transport in kidney cortical slices in terms of its nephrotoxic action.
Cinoxacin is a drug which, at very high doses, causes renal damage only in rats. This study compared the in vitro effects of cinoxacin and nalidixic acid on cellular metabolism and p-aminohippurate (PAH) transport in renal cortical slices. Cinoxacin had no effect on Na+ transport, ATP content, oxygen consumption, inulin space and tissue water content, in rat renal cortical slices in vitro, while nalidixic acid affected most of the parameters tested. PAH uptake by slices from rats pre-treated with a nephrotoxic dose of cinoxacin was decreased. This renal damage appeared to be due to physical trauma resulting from deposition of cinoxacin crystals in the urinary tract.
Aminohippuric Acids↗
Cinoxacin: pharmacokinetics and tolerance in patients with normal and impaired renal function.
The pharmacokinetics of cinoxacin, a new antibacterial compound related to nalidixic acid and oxolinic acid, were investigated in 22 patients with varying degrees of renal impairment. After oral administration of cinoxacin at 500 mg every 12 h for 7 days to all patients, the drug was found to be well tolerated. The urine concentrations of cinoxacin in all patients far exceeded the minimal inhibitory concentrations for susceptible organisms commonly found in urinary tract infections. The serum half-life of cinoxacin in patients with normal renal function was approximately 2.7 h but increased to approximately 8.5 h in patients with creatinine clearance less than 30 ml/min. No undue drug accumulation was demonstrated in any patient group during the treatment. Highly significant correlations were found between the elimination rate constant and creatinine clearance and also between the elimination half-life and serum creatinine. The bioavailability of cinoxacin was independent of renal function.
Aged↗
Single-blind comparison of cinoxacin and nitrofurantoin in the treatment of urinary tract infection.
A single-blind comparison was undertaken to evaluate 250 mg of cinoxacin and 100 mg of nitrofurantoin, both drugs being given four times a day, for the treatment of urinary tract infections. Complete data are available from 58 patients, most of whom were treated for 10 to 15 days. The clinical response was similar in both treatment groups, only one patient in the nitrofurantoin group having a recurrence of symptoms in the posttreatment follow-up period. In one patient in the cinoxacin group, the pathogen was not eradicated, and two patients who received nitrofurantoin had a reinfection with a new pathogen. Four patients stopped treatment early in the study because of side effects attributed to the trial drugs (three on cinoxacin, one on nitrofurantoin). Of the patients who completed the study, only six complained of side effects (two on cinoxacin, four on nitrofurantoin). The results of this study show that cinoxacin is a useful drug for the treatment of urinary tract infection due to susceptible organisms.
Adult↗
Experiences on the efficacy and safety of nalidixic acid, oxolinic acid, cinoxacin and norfloxacin in the treatment of urinary tract infections (UTI).
The purpose of this study was to determine the effectiveness and tolerability of norfloxacin, cinoxacin and oxolinic acid in the treatment of urinary tract infections (UTI) in comparison to nalidixic acid. 125 patients were given the drugs in the appropriate doses for 10-14 days and 30 patients were treated for six weeks. Clinical, bacteriological, hematological and chemical checks were made on all patients before and after treatment. It was found that norfloxacin, cinoxacin and oxolinic acid are safe and effective against Escherichia coli, Klebsiella and Proteus, the commonly encountered organisms in urinary tract infections. The cure rate for norfloxacin was 93%, for cinoxacin 83%, for oxolinic acid 80% and for nalidixic acid 70% in the short course. However, these differences were not statistically significant. Oxolinic acid, cinoxacin and norfloxacin have the advantage over nalidixic acid of being administered only twice daily.
Adolescent↗
Comparative pharmacokinetic profiles of cinoxacin and pipemidic acid in humans.
Serum and urinary levels of Cinoxacin and pipemidic acid were determined at 7-day intervals in the same 10 healthy volunteers after a single oral dose of respectively 500 and 400 mg of the drugs. Comparison of results shows that Cinoxacin was absorbed faster (absorption half-life, ta 1/2cin = 0.25 h) than pipemidic acid (ta 1/2pip = 0.37 h) and distributed in a smaller apparent volume (AVDcin = 23.5 1/1.73 m2; AVDpip = 60.1 1/1.73 m2). Biological half-lives were identical (tb 1/2cin = 2.10 h; tb 1/2pip = 2.15 h). On the other hand, serum levels for Cinoxacin at 1, 2 and 4 hours (8.1 +/- 1.5 micrograms/ml, 10.6 +/- 1.5 micrograms/ml, 5.6 +/- 1.3 micrograms/ml respectively) were higher than those for pipemidic acid (3.3 +/- 0.3 micrograms/ml, 3.4 +/- 0.5 micrograms/ml, 2.1 +/- 0.5 micrograms/ml respectively). Urinary excretion of the two derivatives during the 12 hours following their administration was similar (Ucin0-12h = 86%; Upip0-12h = 83%). Mean urinary concentrations were particularly high, still attaining respectively 90 +/- 29 micrograms/ml and 131 +/- 38 micrograms/ml in samples collected between the 9th and the 12th hours; these levels were well above the M.I.C. for the Gram-negative organisms included within the spectrum of activity of these two quinolones. In addition, predictive calculations of serum levels reached after multiple dosing indicate that at an administration rate of 500 mg every 6 or preferably every 4 hours, Cinoxacin concentrations should be sufficiently high to be of interest in the treatment of systemic infections by sensitive organisms.
Administration, Oral↗
Cinoxacin in urinary tract infections. Theoretical and practical considerations.
In dogs we found that cinoxacin concentrations in prostatic tissue, secretion, and interstitial fluid always were lower than the simultaneous serum concentrations, during constant infusion experiments. The cinoxacin concentrations in urethral and vaginal secretions were similar to those found in prostatic interstitial fluid, approximately one third to one fourth of the simultaneous serum concentrations. The concentrations of cinoxacin in human prostatic tissue after single or multiple doses of 500 mg. were found to be in the range of minimum inhibitory concentrations for most microorganisms found in urinary tract infections. Cinoxacin was found to have a half-life of 2.7 hours in patients with normal renal function, but increased to 8.5 hours in patients with impaired renal function. We found little or no drug accumulation during a seven-day treatment of patients with impaired renal function.
Animals↗