Pharmacokinetics and tissue penetration of orally administered lomefloxacin.

The pharmacokinetics of the quinolone lomefloxacin were determined following a single 400-mg oral dose given to each of six male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were determined by a microbiological assay. Samples from two volunteers were also assayed by high-performance liquid chromatography. The mean peak level in serum, 4.7 micrograms/ml, was attained within 1 h of administration. The mean elimination half-life from serum was 7 h. Inflammatory fluid was penetrated rapidly, with a mean peak level of 3.5 micrograms/ml occurring after 2.7 h. The mean recovery of lomefloxacin from urine over 48 h was 76% of the administered dose. There was a minor peak on the high-performance liquid chromatography trace, suggesting a small amount of unidentified metabolite. This was present only in urine; no detectable metabolites were found in serum. This study suggests that either once-daily or twice-daily dosage of lomefloxacin should be sufficient to treat urinary or systemic infections, respectively, caused by susceptible pathogens.     

Steady-state pharmacokinetics and sputum penetration of lomefloxacin in patients with chronic obstructive pulmonary disease and acute respiratory tract infections.

Oral doses of 400 mg of lomefloxacin were administered once daily prior to breakfast to 10 middle-aged to elderly hospitalized patients with chronic obstructive pulmonary disease during treatment for bronchopulmonary infections. Serial plasma and sputum samples and fractional urine samples were obtained over a steady-state dosing interval. Lomefloxacin concentrations were determined in duplicate by a validated agar well diffusion microbiological assay. The maximum plasma lomefloxacin concentration (4.5 +/- 1.8 mg/liter), the time of occurrence of the maximum concentration (1.7 +/- 1.6 h), and the apparent volume of distribution associated with the terminal phase (2.19 +/- 1.05 liter/kg) were comparable to the values reported for healthy, young volunteers. Compared with the data reported for young adults, the elimination half-life (12.7 +/- 4.67 h) was longer and the apparent total body clearance (132 +/- 36.6 ml/min/1.73 m2) was lower in middle-aged to elderly patients. These differences were most likely attributable to age-related decreases in renal function, as evidenced by the lower lomefloxacin renal clearance (70.3 +/- 33.5 ml/min) in patients. The presence of acute respiratory infection per se did not appear to alter lomefloxacin pharmacokinetics. The peak lomefloxacin concentration in purulent, expectorated sputum samples of 4.3 +/- 1.2 mg/liter occurred 3.1 +/- 1.7 h after dose administration and subsequently declined to 1.7 +/- 0.5 mg/liter at the end of the 24-h dosing interval. The percent penetration into sputum, as assessed by comparing the area under the curve for sputum and plasma samples, was 120 +/- 39.8 (range, 70 to 185). The steady-state lomefloxacin concentrations in plasma and sputum samples from ill, older patients were in excess of the MICs for 90% of the strains tested of common, susceptible respiratory pathogens over most of the dosing interval.     

Lack of interaction between lomefloxacin and caffeine in normal volunteers.

Sixteen healthy, nonsmoking adult males participated in a randomized, double-blind, placebo-controlled, two-way crossover study to evaluate the influence of chronic lomefloxacin administration on the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions. Lomefloxacin (400 mg) or placebo was administered orally once daily for 5 days to xanthine-free volunteers after an overnight fast. Caffeine (200 mg orally) was administered simultaneously with lomefloxacin on days 3 through 5. After a 2-day washout period, subjects were crossed over to the alternate 5-day regimen with caffeine, which was again given on the final 3 days. Blood samples for caffeine, paraxanthine, and lomefloxacin concentration determinations were serially collected for 48 h following the last dose of each regimen. All compounds were analyzed by high-performance liquid chromatography. For the placebo versus lomefloxacin-containing treatments, maximum caffeine concentrations in plasma (4.35 +/- 0.63 versus 4.07 +/- 0.56 micrograms/ml), areas under the concentration-time curve from time zero to 24 h at steady state (30.3 +/- 6.9 versus 29.7 +/- 6.6 micrograms.h/ml), and elimination half-lives of caffeine (4.8 +/- 1.1 versus 4.8 +/- 1.2 h) were not significantly different. In addition, there were no significant changes in the disposition parameters of paraxanthine as a result of lomefloxacin administration. The frequencies of central nervous system-related effects for the two treatments were not statistically different. We conclude that lomefloxacin has no significant effect on the disposition of caffeine in young healthy volunteers.     

The pharmacokinetics of lomefloxacin in elderly patients with urinary tract infection following daily dosing with 400 mg.

Eleven elderly patients (mean age 83 years; range 75-90) with microbiologically proven urinary tract infections were given 400 mg lomefloxacin as a single daily dose for up to seven days. On the first and final day of treatment blood was taken at timed intervals and drug concentration-time curves plotted. Blood was also taken immediately before each of the other doses for assay of pre-dose concentrations. The mean (+/- S.D.) peak serum concentration of lomefloxacin on the first day was 4.8 mg/l (+/- 1.5) observed at a mean of 156 min (+/- 88) and on the final day was 6.3 mg/l (+/- 2.5) at a mean of 119 min (+/- 68). The mean serum half-life on the first day was 10.0 h (+/- 2.8) and on the final day 10.3 h (+/- 2.5). The daily pre-dose serum concentrations of lomefloxacin showed no accumulation of the drug. No serious adverse events were reported and all patients were cured although two had persistent pyuria. It is suggested that a once daily dose of 400 mg lomefloxacin is suitable for the elderly and that no dosage modification is needed in this patient group.     

A comparison of the photosensitizing potential of trovafloxacin with that of other quinolones in healthy subjects

Treatment with some quinolones is associated with an abnormal skin reaction following exposure to sunlight (photosensitivity). The objective of the current study was to compare the photosensitizing potential of a new quinolone, trovafloxacin, with that of ciprofloxacin, lomefloxacin and placebo. Forty-eight healthy males (age range 19-45 years) were randomized to receive a 7 day course of treatment with: (i) trovafloxacin 200 mg od; (ii) ciprofloxacin 500 mg bd; (iii) lomefloxacin 400 mg od; or (iv) placebo bd. Minimal erythema doses (MEDs) were assessed using a monochromator at baseline and on day 5 of treatment, for wavelengths of 305 +/- 5, 335 +/- 30, 365 +/- 30, 400 +/- 30 and 430 +/- 30 nm; 335 +/- 30 and 365 +/- 30 nm are within the UVA range. Immediate reaction MEDs were similar in all treatment groups. However, between baseline and day 5, the mean decreases in delayed-reaction MED (24 h) at 335 +/- 30 nm were only 18.99% for trovafloxacin versus placebo (P = 0.1267), compared with 53.77% (P 0.0001) and 64.13% (P 0.0001) for ciprofloxacin and lomefloxacin, respectively. Similarly, at 365 +/- 30 nm, trovafloxacin produced the smallest reduction in delayed MED versus placebo (43.66%), compared with ciprofloxacin (61.53%) and lomefloxacin (75.81%). These differences between trovafloxacin and ciprofloxacin and lomefloxacin were significant at both 335 +/- 30 and 365 +/- 30 nm (P 0.029). All MED values returned to baseline levels within 2 days of drug cessation. These results show that trovafloxacin has significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin. This photosensitivity appears to be induced only by wavelengths in the UVA region, is maximal at 24 h and is a short-term effect.     

Interaction study of lomefloxacin and ciprofloxacin with omeprazole and comparative pharmacokinetics.

To assess whether or not concomitant omeprazole treatment influences the pharmacokinetics of lomefloxacin and ciprofloxacin, a randomized, double-blind four-way-crossover study was performed. Another objective was to compare the pharmacokinetics of lomefloxacin and ciprofloxacin. Twelve healthy volunteers participated. On days 1 to 4 of each study period, each of them took 20 mg of omeprazole or a placebo orally, and on day 4, each took 400 mg of lomefloxacin or 500 mg of ciprofloxacin orally. Blood and urine samples were collected and assayed for the quinolones by high-pressure liquid chromatography. The mean peak concentrations in plasma (Cmax) and the areas under the curves (AUC), respectively, of lomefloxacin and ciprofloxacin, respectively, after prior treatment with placebo were 2.88 +/- 0.73 (mean +/- standard deviation) as against 2.60 +/- 0.76 micrograms/ml and 24.9 +/- 3.13 as against 11.9 +/- 1.89 micrograms.h/ml, and 72.4% +/- 5.10% as against 36.1% +/- 7.50% of the doses of lomefloxacin and ciprofloxacin, respectively, were recovered from the urine. None of the pharmacokinetic parameters differed significantly after prior treatment with omeprazole compared with placebo. The Cmax of lomefloxacin was not significantly higher than that of ciprofloxacin, but lomefloxacin's AUC reached twice that of ciprofloxacin because of its significantly longer half-life in plasma (6.68 +/- 1.94 as against 4.15 +/- 0.92 h, respectively, P < or = 0.01). Concomitant therapy with omeprazole did not alter the pharmacokinetics of lomefloxacin or ciprofloxacin in these single-dose studies.     

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses.

The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.     

Antimicrobial effects of lomefloxacin in vitro.

The MIC of lomefloxacin was determined for 554 isolates from the urinary tract. Some of the more resistant strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa were studied in a dynamic in-vitro model in order to study dosing strategies. The model simulated, in Mueller-Hinton broth, the profile of plasma lomefloxacin concentrations in volunteers. Bacteria were exposed to a range of lomefloxacin concentration profiles achievable by oral dosing. The first dose of lomefloxacin was rapidly bactericidal in a dose-dependent manner for all strains. On re-exposure, a dose-dependent inhibitory effect was observed. Drug-resistant mutants were readily isolated from all bacteria tested on lomefloxacin-containing plates. These occurred at a high frequency in P. aeruginosa (10(-1)), but less frequently in K. pneumoniae (10(-3)). P. mirabilis (10(-5)), and E. coli (10(-6)). The number of resistant mutants isolated tended to be lower with use of higher drug concentrations. The results suggest that lomefloxacin dosing regimens ensuring maintenance of a high serum concentration: MIC ratio will result in maximal antibacterial effects and minimal problems with resistant strains.     

DETERMINATION OF LOMEFLOXACIN IN BIOLOGICAL FLUIDS BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND A MICROBIOLOGICAL METHOD

A high-performance liquid chromatographic method (HPLC) was developed for the determination of lomefloxacin in plasma and urine and was compared to a microbiological assay. Lomefloxacin and norfloxacin (internal standard) were extracted from plasma and urine samples using chloroform. Measurements were carried out with a fluorescence detector using an excitation wavelength of 280 nm and an emission wavelength of 430 nm with a mercury lamp. Quantification was achieved by the measurement of the peak-height ratio and the analytical recovery of the drug from plasma and urine was found to be (mean +/- SD) 99.3 +/- 3.74% and 95.7% +/- 3.82%, respectively. In the microbiological assay, E. coli ATCC 1346 was the test organism using an agar diffusion technique. The coefficients of variation for within-day analysis for both the HPLC method and microbiological assay from plasma samples were less than 7%. The minimum detectable concentration for both the HPLC and the microbiological method was 50 ng/ml and 100 ng/ml, respectively. Both methods were used to determine the lomefloxacin level in plasma following intravenous administration to mice. Excellent agreement was obtained between the results of the two methods. The HPLC method offers significant advantages in accuracy, precision, speed of analysis and turnover-time.     

Mechanism of action of lomefloxacin.

The inhibition of supercoiling activity of reconstituted Escherichia coli DNA gyrase by lomefloxacin, ciprofloxacin, and norfloxacin was determined. The concentrations of quinolones needed to inhibit DNA synthesis in Escherichia coli, Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were also measured. The kinetics of uptake of [14C]lomefloxacin and unlabeled lomefloxacin into whole cells of E. coli KL-16 and S. aureus NCTC 8532 and the induction of RecA in E. coli GC2241 were assayed. All strains had wild-type susceptibilities to quinolones. The concentration of quinolones needed to inhibit DNA synthesis by 50% correlated with the MIC for members of the family Enterobacteriaceae and P. aeruginosa. The concentration of quinolones needed to inhibit DNA synthesis by 50% for late-logarithmic-phase S. aureus also correlated with the MIC, unlike the data from early-logarithmic-phase cultures. E. coli and S. aureus showed a similar pattern of uptake kinetics of [14C]lomefloxacin and unlabeled lomefloxacin, indicating that the difference in the susceptibilities of the two species is probably due to different target site affinities. Essentially, lomefloxacin was less active than ciprofloxacin and ofloxacin and had activity similar to those of norfloxacin and enoxacin.     

Lomefloxacin pharmacokinetics in subjects with normal and impaired renal function.

Lomefloxacin pharmacokinetics were investigated in 6 normal subjects and 24 uremic patients after a single oral dose of 400 mg. In subjects with normal renal function, the peak level in plasma averaged 3.5 +/- 0.9 micrograms/ml (mean +/- standard deviation) and was obtained at 1.3 +/- 0.9 h. The absorption rate constant was 3.8 +/- 1.6 h-1. The terminal half-life was 7.77 +/- 0.95 h. The apparent volume of distribution was 2.54 +/- 0.66 liters/kg. Total body and renal clearances were 259 +/- 83 and 200 +/- 55 ml/min per 1.73 m2, respectively. The percentage of the dose recovered unchanged in 48-h urine was 80.6 +/- 2.8. In uremic patients, the terminal half-life increased in relation to the degree of renal failure: from 8 h in normal subjects to 38 h in severely uremic patients (glomerular filtration rate, less than 10 ml/min). Renal insufficiency did not significantly modify the peak level in plasma, the time to peak, the apparent volume of distribution, or the nonrenal clearance of lomefloxacin. The dialysis clearance of lomefloxacin was 54 +/- 13 ml/min. Linear relationships were found between lomefloxacin pharmacokinetic parameters and glomerular filtration rate data. Dosage adjustments are necessary in uremic patients.     

Pharmacokinetics of lomefloxacin in renally compromised patients

The single-dose pharmacokinetics of orally administered lomefloxacin (400 mg) were studied in normal subjects and in patients with various degrees of renal function. The subjects were classified by creatinine clearance (CLCR) normalized for body surface area: group 1, CLCR of greater than 80 ml/min/1.73 m2; group 2, CLCR of 80 to greater than 40 ml/min/1.73 m2; group 3, CLCR of 40 to greater than 10 ml/min/1.73 m2; and group 4, CLCR of less than or equal to 10 ml/min/1.73 m2. Each group consisted of eight subjects. The pharmacokinetics of lomefloxacin were significantly influenced by renal function. There were significant differences in the elimination rate constant, half-life, area under the concentration-time curve from 0 h to infinity, apparent total drug clearance, renal clearance, and apparent nonrenal drug clearance between the four renal function groups. Mean half-lives for groups 1, 2, 3, and 4 were 8.09, 9.11, 20.90, and 44.25 h, respectively. There were no significant differences between the renal groups for maximum concentration of the drug in serum and apparent volume of distribution. Age had no apparent effect on lomefloxacin disposition. There was a significant relationship between CLCR and lomefloxacin total body clearance (r = 0.92, P = 0.001) and renal clearance (r = 0.94, P = 0.001). Despite a predominate renal route of elimination, nonrenal lomefloxacin clearance significantly decreased with decreasing renal function (r = 0.72, P = 0.001). Mean lomefloxacin excretion rates over 48 h were 60.7, 56.0, 29.1, and 1.0% of the administered dose for groups 1, 2, 3, and 4, respectively. Mean glucuronide excretion rates over 48 h were 7.8, 6.3, 10.0, and 0.6% of the administered dose for groups 1, 2, 3, and 4, respectively. Hemodialysis had no effect on lomefloxacin concentrations in plasma. In patients with normal to moderate renal function, 400 mg of lomefloxacin per day should provide therapeutic concentrations in blood. The lomefloxacin dose should be reduced to 200 mg/day as the CL(CR) falls below 30 ml/min/1.73 m2. No additional dosage adjustments appear to be necessary for hemodialysis patients.     

Effect of lomefloxacin on theophylline pharmacokinetics.

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.     

Concentrations of oral lomefloxacin in serum and bronchial mucosa.

The bronchial mucosal concentrations of lomefloxacin were determined for specimens obtained by fiber-optic bronchoscopy and compared with simultaneous concentrations in serum. The 23 patients studied were given an oral dose of 400 mg once daily for 4 days to achieve steady-state levels. The median concentration in serum was 2.5 micrograms/ml (range, 1.0 to 5 micrograms/ml), and the median bronchial mucosal concentration was 5.0 micrograms/g (range, 0.7 to 18.6 micrograms/g). The median percent penetration was 177% (range, 69 to 541%). The concentrations in serum and mucosa exceeded the MIC for 90% of strains of organisms causing bronchial infections but not sufficiently to recommend lomefloxacin for the routine treatment of pneumococcal infections.     

Carbohydrate and fat have different effects on plasma leptin concentrations and adipose tissue leptin production

Leptin is secreted by adipocytes and plays a role in the regulation of food intake. However, the regulation of leptin production by adipose tissue is unclear. We have investigated whether a mixed meal or a high-fat load given orally, or a pure fat load given intravenously, stimulates adipose tissue leptin production. Six volunteers were studied on two occasions following an overnight fast. On one occasion they consumed tomato soup containing 40 g of triacylglycerol (as Intralipid) and 9.6 g of carbohydrate; on the other occasion Intralipid was infused intravenously over 4 h to give the same fat load. A further eight subjects consumed a mixed meal (containing 37 g of fat and 100 g of carbohydrate) after an overnight fast. Paired blood samples were obtained from an arterialized hand vein and a vein draining subcutaneous adipose tissue at baseline and for 6 h following the meals or the start of the infusion. After both the intravenous and oral fat loads, the arterialized and adipose venous plasma leptin concentrations decreased over 6 h (both P<0.001), as did the leptin veno--arterial difference (P=0.01). Following the mixed meal, there was a slight increase in the arterialized plasma leptin concentration (P=0.02) and a more marked increase in the adipose venous plasma leptin concentration (P=0.03) and in the adipose tissue leptin veno--arterial difference (P=0.01), all peaking at 240 min. We conclude that the increase in plasma leptin concentration observed after meals is not simply a result of an energy load, but is in response to a signal that is not present following a fat load without carbohydrate.     

Lomefloxacin, a new fluoroquinolone. Studies on in vitro antimicrobial spectrum, potency, and development of resistance

Lomefloxacin (NY-198; SC-47111), a potent new difluoroquinolone, was studied to compare its in vitro activity with that of other antimicrobials against 2194 clinical isolates. Lomefloxacin showed excellent inhibitory and bactericidal activity against strains of Enterobacteriaceae and inhibited greater than 99% of the isolates at a concentration of 4 micrograms/ml or less. Lomefloxacin exhibited good-to-moderate activity against strains of Acinetobacter (MIC90 4 micrograms/ml) and Pseudomonas aeruginosa (MIC90 8 micrograms/ml), but poor activity for Pseudomonas cepacia (MIC90 greater than 16 micrograms/ml). Staphylococcus aureus, and Staphylococcus epidermidis isolates, both oxacillin-susceptible and -resistant strains, were susceptible (MIC90 1 micrograms/ml) to lomefloxacin and the other fluoroquinolones. Strains of Haemophilus influenzae, (MIC90 less than or equal to 0.13 micrograms/ml) Neisseria gonorrhoeae (MIC90 less than or equal to 0.03 micrograms/ml), and Branhamella catarrhalis (MIC90 less than or equal to 0.03 micrograms/ml) were highly susceptible to lomefloxacin. Streptococcal isolates, especially viridans streptococci, were considerably less susceptible to the fluoroquinolones. Overall, lomefloxacin had comparable activity to norfloxacin, fleroxacin, and ofloxacin, and against many facultative anaerobes lomefloxacin was more active than imipenem, cefotaxime, ceftazidime, ticarcillin/clavulanic acid, aztreonam, trimethoprim/sulfamethoxazole and gentamicin. Development of resistance to lomefloxacin by spontaneous mutation was low and comparable to that of other fluoroquinolones. Growth in subinhibitory concentrations resulted in increased resistance to fluoroquinolones for selected test strains.     

Intraprostatic distribution of lomefloxacin following multiple-dose administration.

The ability of lomefloxacin to penetrate and distribute within the human prostate was assessed in 20 patients undergoing elective prostate surgery (18 transurethral prostatic resections and 2 prostatectomies). Subjects were middle-aged to elderly (mean age +/- standard deviation, 69.8 +/- 8.2 years) with normal hepatic function and with creatinine clearances ranging from 35.8 to 141 ml/min/1.73 m2. Lomefloxacin was administered in 400-mg doses orally every 24 h. Its disposition was characterized following the third dose by obtaining multiple serum samples and intraoperative paired central zone and peripheral zone prostate tissue samples. Lomefloxacin concentrations were determined by a validated high-performance liquid chromatography method with fluorescence detection. Concentrations in serum during the perioperative period declined from 3.1 +/- 1.0 mg/liter (mean +/- standard deviation) at 1 h postdose to 2.3 +/- 0.7 mg/liter at 6 h postdose. The time of tissue extraction ranged from 0.1 to 7.1 h postdose. Intraoperative serum lomefloxacin concentrations ranged from 0.5 to 4.8 (median, 2.4) mg/liter, while prostate tissue concentrations ranged from 1.1 to 10.1 (median, 5.4) mg/kg of tissue for the central zone and 0.9 to 6.5 (median, 5.2) mg/kg for the peripheral zone. Intraindividual paired prostate concentrations (central zone versus peripheral zone) were not statistically different. The partition coefficient (ratio of concentration in prostate to concentration in serum) for the central zone was 2.2 +/- 0.6 (range, 1.2 to 3.1), and for the peripheral zone it was 2.1 +/- 0.7 (range, 1.2 to 4.2). Lomefloxacin exhibited good penetration into the human prostate with homogeneous intraprostatic distribution following multiple-dose administration.     

Effect of a fat- and calcium-rich breakfast on pharmacokinetics of fleroxacin administered in single and multiple doses.

The effect of a fat- and liquid-calcium-rich meal on the pharmacokinetics of single and multiple doses of fleroxacin in 20 healthy men and women was investigated in a randomized crossover fashion. Fleroxacin was administered as 400 mg daily for 3 days and as a single 400 mg dose. Concurrent administration of fleroxacin with food resulted in a statistically significant (P < or = 0.05) decrease in the area under the curve (13.9% for multiple-dose administration, 10% for single-dose administration) and in the peak concentration (25.9% for multiple-dose administration, 27% for single-dose administration) and a lengthening of the time to peak (more than doubled for single- and multiple-dose phases). In addition, by using an equivalence criteria of 80 to 125%, the two one-sided tests procedure indicated that the mean areas under the curves for fleroxacin administered in a fed and a fasted state were statistically bioequivalent (P < or = 0.05) for both the single- and multiple-dose regimens. Although a meal high in fat and containing liquid calcium reduces the peak concentration by approximately 25%, a minimal effect on bioavailability is seen with concomitant food administration. In addition, multiple-dose bioavailability studies appear to give similar information to single-dose studies while representing the clinical setting more closely.     

A gut-specific serine protease from the malaria vector Aanopheles gambiae is downregulated after blood ingestion

A chymotrypsin-like serine protease gene (AgChyL) was cloned from the mosquito Anopheles gambiae by a polymerase chain reaction (PCR)-based subtractive cDNA cloning strategy. AgChyL messenger RNA (mRNA) is abundant in the adult female gut prior to, and for 8 h following, a blood meal. During the peak of digestion, from 12 to 24 h following a blood meal, AgChyL mRNA abundance decreased to barely detectable levels. AgChyL mRNA was abundant again by 48 h following a blood meal. Recombinant pro-AgChyL was expressed in Escherichia coli. The pro-enzyme can be activated by trypsin. Activated AgChyL cleaves the synthetic chymotrypsin substrate succinyl-L-Ala-Ala-Pro-Phe-nitroanilide, but not two other synthetic chymotrypsin substrates or synthetic trypsin and elastase substrates. The potential role of AgChyL in the coordination of An. gambiae digestion is discussed.     

Treatment of acute uncomplicated urinary tract infections with 3 days of lomefloxacin compared with treatment with 3 days of norfloxacin.

The bacteriologic and clinical efficacies of 3 days of lomefloxacin therapy were compared with those of 3 days of norfloxacin therapy for the treatment of acute uncomplicated urinary tract infections in a prospective, randomized, double-blind study. One hundred sixty-four subjects were enrolled at five Canadian centers; 84 received lomefloxacin, and 80 received norfloxacin. Escherichia coli (84%) and Staphylococcus saprophyticus (11%) were the most common organisms isolated. Forty subjects (24%) had low quantitative counts in their pretherapy urine specimens. In the intent-to-treat analysis, 76 lomefloxacin subjects (91%) and 76 norfloxacin subjects (95%) were cured or improved at follow-up 5 to 9 days posttreatment and 73 (87%) and 71 (89%) subjects from the lomefloxacin and norfloxacin groups, respectively, were cured or improved at 4 to 6 weeks posttreatment. Bacteriologic eradication occurred in 61 of 63 lomefloxacin subjects (97%) with > or = 10(8) CFU/liter in their pretherapy specimens and 56 of 59 norfloxacin subjects (95%) at 5 to 9 days and 55 (87%) and 53 (90%) subjects from the lomefloxacin and norfloxacin groups, respectively, at 4 to 6 weeks. There were no statistically significant differences in outcome. Adverse effects which were potentially related to the study medications were reported by 26% of the subjects who received lomefloxacin and 25% of the subjects who received norfloxacin. There were no severe adverse events, and only one subject discontinued therapy. These data suggest that 3 days of therapy with either lomefloxacin or norfloxacin is effective in the treatment of acute uncomplicated urinary tract infections.