The effect of terfenadine on the cardiac pharmacodynamics of sparfloxacin.

This double-masked, randomized, placebo-controlled study was conducted to assess the effect of concomitant administration of terfenadine and sparfloxacin on the electrocardiographic (ECG) QT(c) interval in healthy volunteers, before the removal of terfenadine from the market. Eighty-eight men (aged 18 to 49 years, weighing 60.0 to 98.6 kg) with no clinically relevant ECG abnormalities received placebo, sparfloxacin (400 mg on day 1, 200 mg daily on days 2-4), terfenadine (60 mg BID), or the combination of sparfloxacin and terfenadine. After each dose, serial blood samples and ECG measurements were collected to determine sparfloxacin pharmacokinetic and pharmacodynamic variables. The area under the concentration-time curve and maximum concentration for sparfloxacin were approximately 16% less on day 4 compared with day 1, reflecting the higher plasma level after the 400-mg loading dose compared with that after the maintenance dose of 200 mg daily. Concomitant administration of terfenadine had no effect on these pharmacokinetic variables. When compared with the placebo-adjusted increases in QTc interval in the sparfloxacin (19 milliseconds on day 1 and 14 milliseconds on day 4) and terfenadine (2 milliseconds on day 1 and 7 milliseconds on day 4) treatment groups, the placebo-adjusted increases in QTc interval in the volunteers treated with the combination of sparfloxacin and terfenadine (18 milliseconds on day 1 and 22 milliseconds on day 4) were considered to be additive (no statistically significant interaction). Thus there are no apparent pharmacokinetic or dynamic QTc interactions between terfenadine and sparfloxacin. However, sparfloxacin should be administered with caution to patients receiving concomitant medications known to prolong the QTc interval.

The cardiac pharmacodynamics of therapeutic doses of sparfloxacin.

This double-masked, randomized, placebo-controlled study assessed the cardiac safety of sparfloxacin (as measured by the effect on corrected QT [QTc] interval) at the extremes of the expected therapeutic dosage range. Ninety healthy adult male volunteers with no clinically relevant electrocardiographic (ECG) abnormalities received either placebo or 1 of 3 sparfloxacin regimens consisting of a loading dose on day 1 followed by 3 days of daily dosing at half the loading dose (200/100 mg, 400/200 mg, or 800/400 mg). After each dose, serial blood samples and ECG measurements were obtained to determine the pharmacokinetic and pharmacodynamic variables for sparfloxacin. Increases in the area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) for each dosing interval and in the maximum concentration (Cmax) on days 1 and 4 were dose proportional. The steady-state (day-4) values were 6% to 16% lower than the day-1 values. At steady state, the time to C ranged from 2.5 to 3.9 hours across all doses and days studied. The half-life ranged from 18.7 to 20.3 hours. Increases in the placebo-adjusted mean change and mean maximum change in QTc interval were dose related. The placebo-adjusted increases on day 1 were 9, 16, and 28 milliseconds after receipt of the 200/100-mg, 400/200-mg, and 800/400-mg regimens, respectively. The corresponding increases on day 4 were 7, 12, and 26 milliseconds. The placebo-adjusted changes in QTc interval also showed a linear relationship with the AUC0-24 and Cmax of sparfloxacin. In the majority of volunteers (>90%), these increases were within the normal range for the QTc interval (< or = 460 milliseconds).

Pharmacokinetics of sparfloxacin in patients with renal impairment.

Sparfloxacin is a fluoroquinolone antimicrobial agent with a broad spectrum of activity and long elimination half-life. Because its single-dose pharmacokinetics are altered by renal impairment, the present study was undertaken to determine the effects of moderate or severe renal insufficiency on the multidose pharmacokinetic characteristics of and tolerance to sparfloxacin. The pharmacokinetic characteristics of sparfloxacin were assessed in 32 subjects (15 men, 17 women) with (1) normal renal function (creatinine clearance [CLcr]> or = 250 mL/min per 1.73 m2) and a mean age of 52.6 years and mean weight of 70.4 kg; (2) moderate renal insufficiency (CLcr 30-49 mL/min per 1.73 m2) and a mean age of 54.4 years and mean weight of 67.8 kg; and (3) severe renal insufficiency (CLcr 10-29 mL/min per 1.73 m2) and a mean age of 50.8 years and mean weight of 73.1 kg. The first 2 groups received a 400-mg loading dose on day 1 followed by 200 mg once daily for 9 days; subjects with severe renal insufficiency received a 400-mg loading dose on day 1 followed by 200 mg every 48 hours on days 3, 5, 7, and 9. The plasma and urinary pharmacokinetics of sparfloxacin and its glucuronide metabolite were determined after the last dose. All subjects were monitored for changes in the corrected QT (QTc) interval and for adverse events. Renal insufficiency altered the steady-state pharmacokinetic variables of sparfloxacin and its glucuronide metabolite, reducing their renal clearances and increasing both maximum plasma concentration and area under the plasma concentration-time curve. Mean steady-state plasma sparfloxacin concentrations in subjects with severe renal insufficiency (48-hour dosing interval) were comparable to those in subjects with normal renal function (24-hour dosing interval). However, mean plasma sparfloxacin concentrations in patients with moderate renal insufficiency were 2 to 3 times greater than the corresponding concentrations in subjects with normal renal function receiving the same dosage regimen. The QTc interval was slightly increased in all groups (the greatest increases were 14, 14, and 6 milliseconds in the groups with normal renal function and moderately and severely impaired renal function, respectively, at 5.5 hours post-dose on day 9 or 10) but similar among subjects with normal renal function or with renal insufficiency. Sparfloxacin was well tolerated. Thus sparfloxacin clearance is reduced and plasma concentrations raised by moderate or severe renal insufficiency. These increases do not appear to augment drug effects on the QTc interval or enhance the risk for adverse events. These results suggest that alternate-day dosing (48-hour dosing interval) following a double loading dose on day 1 should be used in patients with severe renal insufficiency and may be appropriate for patients with moderate renal insufficiency.

Comparison of sparfloxacin and ciprofloxacin in the treatment of community-acquired acute uncomplicated urinary tract infection in women. Sparfloxacin Multicenter Uncomplicated Urinary Tract Infection Study Group.

Urinary tract infection (UTI) is a common illness, with > or =30% of all women experiencing a UTI during their lifetime. Less than a decade ago, the standard therapy for acute uncomplicated UTIs involved treatment with > or =7 days of an antibacterial agent, but recent studies using a variety of newly introduced antibiotics, including the fluoroquinolones, have demonstrated that a 1- to 5-day treatment regimen can be equally effective. This randomized, double-masked, multicenter study was conducted to compare the efficacy and tolerability of a single dose of sparfloxacin with those of a 3-day regimen of sparfloxacin and a 7-day regimen of ciprofloxacin in the treatment of women with community-acquired acute uncomplicated urinary tract infection. A total of 1175 women were enrolled; 395 received sparfloxacin as a single 400-mg dose on day 1, 394 received sparfloxacin as a 400-mg loading dose on day 1 followed by 200 mg once daily for 2 additional days, and 386 received ciprofloxacin 250 mg twice daily for 7 days. Patients were comparable with respect to demographic characteristics and underlying conditions. A total of 954 patients were clinically assessable; 490 of these were also bacteriologically assessable. All patients treated were included in the tolerability analysis. Escherichia coli (75.4%), Klebsiella pneumoniae (4.9%), Enterococcus faecalis (4.6%), and Staphylococcus saprophyticus (4.1%) were the most commonly isolated organisms. In the all-treated population, clinical success was achieved 5 to 9 days after therapy in 91.8%, 92.2%, and 91.6% of patients in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; bacteriologic success was observed in 91.7%, 92.6%, and 96.6% of those in the 3 groups. Sustained clinical success rates 4 to 6 weeks after therapy were 76.6%, 80.2%, and 79.5% in the single-dose sparfloxacin, 3-day sparfloxacin, and 7-day ciprofloxacin groups, respectively; sustained bacteriologic success rates were 80.7%, 90.1%, and 92.6%. The most common adverse events were nausea, headache, vaginal thrush, dizziness, and diarrhea; >92% of adverse events were mild or moderate in severity. The 2 drugs had comparable frequencies of adverse events, except for photosensitivity, which occurred in 3.3% of the 3-day sparfloxacin group, 1.3% of the single-dose sparfloxacin group, and 0.3% of the ciprofloxacin group (P = 0.005). The 3-day sparfloxacin regimen was effective and well tolerated. The initial response to single-dose sparfloxacin treatment was comparable to the response to the other 2 regimens, but the single-dose regimen proved less effective over time, with higher rates of clinical recurrence and bacteriologic relapse. Sparfloxacin provides an alternative to ciprofloxacin for patients with acute uncomplicated urinary tract infection who are not at risk for photosensitivity reactions or adverse events associated with a prolonged corrected QT interval.

Effects of food on the pharmacokinetics of sparfloxacin.

Sparfloxacin, a fluoroquinolone with a broad antimicrobial spectrum and long elimination half-life, is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis in adult patients. The present study was undertaken to determine the effects of skim milk and a high-fat breakfast without milk on the single-dose pharmacokinetic characteristics of this antibiotic. The pharmacokinetics of a single 200-mg dose of sparfloxacin were assessed in a 3-way crossover study that included 23 healthy male volunteers who had fasted, had ingested 240 mL of skim milk, or had consumed a standard high-fat breakfast. The subjects' mean age and weight were 26.5 years and 73.2 kg, respectively; 17 were white, 5 Hispanic, and 1 black. Neither skim milk nor the high-fat breakfast had a statistically significant effect on sparfloxacin absorption, as reflected in the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Ninety percent confidence limits for logarithmically transformed AUC from time zero to infinity and Cmax were within the 80% to 125% range, demonstrating that the rate and extent of sparfloxacin absorption with skim milk or a high-fat breakfast were not different from those under fasted conditions. As indicated by an increase in the time to Cmax from 3.6 to 5.4 hours, the high-fat breakfast slightly delayed the onset of sparfloxacin absorption. Skim milk and the high-fat breakfast did not significantly affect the elimination kinetics of sparfloxacin. Sparfloxacin was well tolerated in all 3 treatment groups. Despite the apparent delay in the onset of absorption, the bioavailability of sparfloxacin in the healthy male subjects in this study population was not affected by concomitant administration with skim milk or a high-fat meal. Accordingly, the results suggest that sparfloxacin can be administered without regard to the ingestion of milk or meals.

Comparison of the in vitro activity of and pathogen responses to sparfloxacin with those of other agents in the treatment of respiratory tract, urinary tract, and skin and skin-structure infections.

The in vitro activity of and pathogen responses to sparfloxacin were compared with those of standard therapies for the treatment of patients with community-acquired pneumonia, complicated skin or skin-structure infections, urinary tract infections, acute bacterial exacerbations of chronic bronchitis, and acute maxillary sinusitis in 7 multicenter controlled trials in North America. Sparfloxacin was administered orally as a 400-mg loading dose followed by 200 mg once daily for up to 10 days. The bacteriologic efficacy of sparfloxacin (84% to 95%) was comparable to that of comparator drugs (77% to 100%). Sparfloxacin was generally 2 to 8 times more active (minimum inhibitory concentration for 90% of strains tested [MIC90]: 0.03 to 0.5 microg/mL) than comparators against common pathogens isolated in community-acquired infections, especially Streptococcus pneumoniae, including penicillin-resistant strains; Moraxella catarrhalis; Haemophilus influenzae; Streptococcus pyogenes; and Staphylococcus aureus. Sparfloxacin was also effective against Chlamydia and Mycoplasma species. The emergence of resistance was uncommon during sparfloxacin therapy (0.3% of 1100 cases). Higher area under the plasma concentration-time curve/MIC and maximum plasma concentration/MIC ratios for sparfloxacin were associated with clinical and bacteriologic efficacy, whereas lower ratios were associated with clinical and bacteriologic failure. The clinical efficacy of sparfloxacin (80% to 95%) was comparable to that obtained with the comparator drugs (71% to 92%). In addition, sparfloxacin was well tolerated and had an overall frequency of related adverse events similar to that of the comparators. There was a higher frequency of photosensitivity reactions but a lower level of digestive adverse events with sparfloxacin compared with comparators. Sparfloxacin is a suitable therapeutic alternative for the empiric treatment of respiratory tract infections owing to its favorable pharmacokinetic profile and activity against typical and atypical respiratory tract pathogens, even in geographic areas with a high incidence of penicillin resistance.

Effect of single ascending, supratherapeutic doses of sparfloxacin on cardiac repolarization (QTc interval).

This double-masked, randomized, placebo-controlled study was conducted in healthy adult male and female volunteers with no clinically relevant baseline electrocardiographic (ECG) abnormalities to assess the cardiac tolerability margin of sparfloxacin (as measured by the effect on QTc interval) under conditions of potential overdose at up to 4 times the usual therapeutic loading dose. The 23 enrolled volunteers received a sequence of single doses of sparfloxacin (400, 800, 1200, and 1600 mg), 1 dose in each of 4 study periods. Six volunteers received placebo during each period. A 14-day washout separated the periods. Serial blood samples and ECG measurements were collected in each period to determine the pharmacokinetic and pharmacodynamic characteristics of sparfloxacin. The area under the concentration-time curve from time zero to infinity (AUC0-infinity) exhibited dose proportionality. The maximum plasma concentration (Cmax) after the 1200- and 1600-mg doses was lower than would be expected for a linear dose relationship. This was also the case with the mean increase and mean maximum increase in QTc interval. Increases in the QTc interval correlated well with Cmax but not with AUC0-infinity. The time to reach Cmax showed a slight tendency to increase with dose, as did the terminal elimination half-life. Changes in QTc-interval dispersion were similar for both placebo recipients and sparfloxacin-treated volunteers and were of no clinical consequence. At supratherapeutic doses, the extent of sparfloxacin's absorption (AUC0-infinity) was dose independent; however, the rate of absorption was dose dependent, with Cmax increasing substantially less than proportionally to the administered dose. This limited the Cmax of sparfloxacin at supratherapeutic doses and thus the increase in QTc interval. Rechallenge demonstrated that only 2 of 8 subjects had the same degree of QTc-interval prolongation, emphasizing the marked variability in the QTc interval.

Pharmacokinetic interaction of sparfloxacin and digoxin.

Sparfloxacin, a broad-spectrum, oral fluoroquinolone antimicrobial agent, has a long elimination half-life that permits once-daily administration. Antibiotics may increase the oral bioavailability of digoxin, leading to increases in its plasma concentration. Since patients treated with sparfloxacin may be receiving concurrent treatment with digoxin, the possibility of an interaction between sparfloxacin and digoxin was examined in a double-masked, placebo-controlled, multiple-dose, two-way crossover study in 24 healthy male volunteers between 20 and 49 years of age. All subjects were given digoxin 0.3 mg once daily throughout the 20-day study. Sparfloxacin (or placebo) was given as a 400-mg loading dose on day 1, followed by single 200-mg daily doses for 9 days, with crossover to the alternate treatment on days 11 through 20. Plasma levels of digoxin were analyzed by validated radioimmunoassay, and plasma levels of sparfloxacin were analyzed by validated high-performance liquid chromatography. Concomitant administration of sparfloxacin and digoxin was generally well tolerated. Mean values for steady-state area under the concentration-time curve over 24 hours for the 2 treatments were virtually identical: 28.4 ng/h per mL(-1) for digoxin administered with placebo and 28.9 ng/h per mL(-1) for digoxin administered concomitantly with sparfloxacin. Mean steady-state maximum plasma concentrations were 3.91 and 3.59 ng/mL for digoxin with placebo and digoxin with sparfloxacin, respectively. Mean steady-state trough plasma digoxin concentrations for the 2 treatments were 0.87 and 0.89 ng/mL, respectively. Mean times to steady-state maximum plasma concentrations were identical at 0.89 hours for both treatments. Mean steady-state oral clearance was 10.6 L/h for digoxin alone and 10.4 L/h for digoxin with sparfloxacin. Thus administration of sparfloxacin in combination with digoxin did not alter the pharmacokinetics of digoxin in healthy male volunteers aged 20 to 49 years. Steady-state plasma sparfloxacin concentrations were consistent with those obtained in other multiple-dose phase I studies, suggesting that digoxin does not alter the steady-state pharmacokinetics of sparfloxacin.

Safety profile of sparfloxacin, a new fluoroquinolone antibiotic.

The safety profile of sparfloxacin, a newer fluoroquinolone antibiotic, was examined through an integrated analysis of safety data from 6 multicenter phase III trials. These consisted of 5 double-masked, randomized, comparative trials of sparfloxacin (a 400-mg oral loading dose followed by 200 mg/d for 10 days) versus standard therapies (erythromycin, cefaclor, ofloxacin, clarithromycin, and ciprofloxacin) and I open-label trial (noncomparative) in patients with: community-acquired pneumonia (2 trials); acute bacterial exacerbations of chronic bronchitis (1 trial); acute maxillary sinusitis (2 trials, one of which was the noncomparative trial); and complicated skin and skin-structure infections (1 trial). Overall, 401 (25.3%) of 1585 patients treated with sparfloxacin and 374 (28.1%) of 1331 receiving a comparator regimen experienced at least 1 adverse event considered to be related to the study medication. Photosensitivity reactions, usually of mild-to-moderate severity, were seen more frequently with sparfloxacin (7.4%) than with comparator agents (0.5%), whereas gastrointestinal reactions (diarrhea, nausea, dyspepsia, abdominal pain, vomiting, and flatulence), insomnia, and taste perversion were more common in patients taking comparator drugs (22.3% vs 12.1%, 4.3% vs 1.5%, and 2.9% vs 1.2%, respectively). Analysis of electrocardiographic findings showed that the mean change from baseline in QT interval corrected for heart rate (QTc) was significantly greater in sparfloxacin-treated patients (10 msec) than in patients given comparator drugs (3 msec), but no associated ventricular arrhythmias were detected. Adverse events led to discontinuation of study medication in 104 (6.6%) patients receiving sparfloxacin and 118 (8.9%) given com parator drugs. Sparfloxacin may be considered an appropriate choice for the treatment of certain community-acquired infections for patients who are not at risk for photosensitivity reactions or adverse events associated with prolongation of the QTc interval.

Treatment of community-acquired acute uncomplicated urinary tract infection with sparfloxacin versus ofloxacin. The Sparfloxacin Multi Center UUTI Study Group.

The efficacy and safety of a 3-day regimen of sparfloxacin were compared with those of a 3-day regimen of ofloxacin for the treatment of community-acquired acute uncomplicated urinary tract infections. Four hundred nineteen women were enrolled in a randomized, open-label, observer-blinded, multicenter study; 204 received sparfloxacin as a 400-mg loading dose on the first day and 200 mg once daily thereafter, and 215 received ofloxacin as 200 mg twice daily. A total of 383 patients met the criteria for clinical evaluability, and 174 were also bacteriologically evaluable; all treated patients were included in the safety analysis. Escherichia coli (86%) and Staphylococcus saprophyticus (4.6%) were the organisms most commonly isolated. Positive clinical responses were obtained 5 to 9 days after therapy in more than 92% of the patients in each group; sustained clinical cure rates 4 to 6 weeks after therapy were 78.3 and 76.9% in the sparfloxacin and ofloxacin groups, respectively. A positive bacteriologic response was observed in 98% of the bacteriologically evaluable patients in each treatment group at 5 to 9 days posttherapy and in 88.2 and 92.6% of the patients in the sparfloxacin and ofloxacin groups, respectively, 4 to 6 weeks after therapy. Almost 90% of all adverse events were of mild or moderate severity; the most frequent events at least possibly related to drug treatment were those common to the fluoroquinolones, namely, nausea, diarrhea, headache, insomnia, and photosensitivity. Photosensitivity was more frequent in the sparfloxacin group (6.9% versus 0.5% in the ofloxacin group); insomnia was more frequent in the ofloxacin group (3.7% versus 1.0% in the sparfloxacin group). These data suggest that a once-daily, 3-day regimen of sparfloxacin is effective and generally well tolerated in the treatment of acute uncomplicated urinary tract infections.

Effect of Maalox on the oral absorption of sparfloxacin.

Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life (t(1/2)). Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones. This study was undertaken to determine an optimal time for dosing antacids in relation to sparfloxacin administration to minimize antacid-induced reduction in sparfloxacin bioavailability. This open-label, single-dose, randomized, four-way crossover study was conducted in 20 healthy male volunteers between the ages of 18 and 38 years. Treatments consisted of single 400-mg oral doses of sparfloxacin alone and with Maalox 30 mL given 2 hours before, 2 hours after, and 4 hours after oral administration of sparfloxacin. All 20 subjects completed the study. A 400-mg single oral dose of sparfloxacin was well tolerated both given alone and with Maalox. Maalox given 4 hours after sparfloxacin administration was the only regimen that did not cause a statistically significant reduction in the rate and extent of sparfloxacin absorption. The 90% confidence intervals comparing sparfloxacin alone with the preceding regimen in terms of area under the concentration-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (Cmax) were within the range 80% to 125%. Administration of Maalox 2 hours before, 2 hours after, and 4 hours after sparfloxacin caused mean decreases in AUC(0-infinity) of 23%, 17%, and 5%, respectively. Corresponding decreases in mean Cmax values were 29% with Maalox administered 2 hours before sparfloxacin and 13% with Maalox administered 2 hours after sparfloxacin. The mean Cmax value was un affected when Maalox was administered 4 hours after sparfloxacin administration. The 90% confidence intervals for these comparisons with sparfloxacin alone were outside the 80% to 125% range and did not include 100%. Time to Cmax and t(1/2) were similar for all four regimens. The elimination rate of sparfloxacin was unaffected by concomitant administration with Maalox in healthy male volunteers.

The effect of food on the bioavailability of ebastine.

Two studies were performed to characterize the influence of food on the bioavailability of the current formulation of ebastine tablets. Study 1 was an open label, randomized, three-period, crossover food effect study where 18 healthy male volunteers received 10 mg ebastine after an overnight fast, a low-fat breakfast, and a high-fat breakfast. Study 2 was an open label, randomized, two period crossover food effect study where 12 healthy male volunteers received 20 mg ebastine after both an overnight fast and a high-fat breakfast. Plasma samples were obtained at selected times and analyzed for ebastine and carebastine, the active metabolite of ebastine, using a validated high-performance liquid chromatography assay. Biopharmaceutic parameters for carebastine, area under the plasma concentration-time curves (AUC (0-infinity)), and maximum plasma concentrations (C ( max ) ), were estimated using noncompartmental techniques and analyzed for statistical differences. AUC (0-infinity) and C(max estimates were 40%-50% and 30%-40% higher under fed conditions as compared with fasting conditions. The time to reach maximum concentrations (T(max)), the terminal elimination rate (K(e) ), and the half-life (t(1/2) ) were not significantly altered by the ingestion of a low-fat or high-fat meal. Statistical analyses of the natural logarithmic transformed data for AUC ((0-infinity) and C(max) also demonstrated significant differences between fasted and fed (low-fat and high-fat) conditions. This indicates that food had a statistically significant effect on the rate and extent of carebastine formation. Therefore, it may be concluded that administration with food maximizes the bioavailability of carebastine.

The tolerance and pharmacokinetics of clinafloxacin (CI-960) in healthy subjects.

The single-dose tolerance and pharmacokinetics of clinafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Single oral doses of 25, 50, 100, and 200 mg were well tolerated. Adverse events after placebo and clinafloxacin were similar, with mild drowsiness, dizziness, headache, and rash being reported most frequently. The frequency and intensity of side-effects did not increase with dose. Clinafloxacin was rapidly absorbed, with Cmax occurring at approximately 40 min postdose. Plasma concentrations increased proportionately and, following 100 or 200 mg doses, remained above MIC90s required for most nosocomial pathogens for at least 12 h. Clinafloxacin elimination half-life averaged 5.2 h and renal clearance was approximately 200 mL/min. About 50% of the administered dose was excreted unchanged in the urine.

In vitro activity of sparfloxacin (CI-978; AT-4140) for clinical Legionella isolates, pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia.

The activities of sparfloxacin, ciprofloxacin, and erythromycin for 21 clinical Legionella isolates were determined by agar and broth dilution susceptibility testing and by growth inhibition assays in guinea pig alveolar macrophages (sparfloxacin and ciprofloxacin). All three antimicrobial agents had roughly equivalent activities when buffered charcoal yeast extract agar medium supplemented with 0.1% alpha-ketoglutarate was used as the test medium; the MICs for 90% of strains were 1.0 micrograms/ml for erythromycin and sparfloxacin and 0.5 microgram/ml for ciprofloxacin. Buffered charcoal yeast extract medium supplemented with 0.1% alpha-ketoglutarate inhibited the activities of all the antimicrobial agents tested, as judged by the susceptibility of a control Staphylococcus aureus strain. Broth macrodilution MICs for two L. pneumophila strains in buffered yeast extract supplemented with 0.1% alpha-ketoglutarate were less than or equal to 0.03 microgram/ml for sparfloxacin, 0.06 microgram/ml for ciprofloxacin, and 0.25 microgram/ml for erythromycin; only erythromycin was inhibited by this medium. Ciprofloxacin and sparfloxacin (both 0.25 microgram/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 log10 CFU/ml, but regrowth occurred over a 3-day period. Sparfloxacin, but not ciprofloxacin (both 1 microgram/ml), caused a 3- to 4-day postantibiotic effect. Pharmacokinetic and therapy studies of sparfloxacin were performed in guinea pigs with L. pneumophila pneumonia. For the pharmacokinetic study, sparfloxacin was given (10 mg/kg of body weight) to infected guinea pigs by the intraperitoneal route; peak levels in serum and lung were 2.6 micrograms/ml and 1.6 micrograms/g, respectively, at 1 h, with a terminal-phase half-life of elimination from serum of 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific assay for the quantitation of indocyanine green in rat plasma using high-performance liquid chromatography with fluorescence detection.

A rapid and sensitive reversed-phase HPLC assay employing fluorescence detection was developed for quantitating indocyanine green (ICG) in rat plasma. Sample preparation entailed precipitation of plasma proteins with acetonitrile prior to injection on the column. The assay was linear from 0.4 to 200 micrograms/mL, with a detection limit of 3 ng on column. The plasma concentration-time profile of ICG was characterized by this HPLC method and compared with the traditional spectrophotometric assay following iv bolus and iv infusion administration of 5 mg/kg of ICG to rats. Concentrations of ICG obtained using the spectrophotometric assay were consistently higher than those determined by HPLC. In animals receiving ICG by infusion, the maximum difference between the two assays was observed 1 min post-infusion and became negligible by 5 min post-infusion. The calculated pharmacokinetic parameters for ICG, systemic clearance and apparent volume of distribution, were higher using the HPLC assay as compared with the spectrophotometric procedure. The data suggest that a biotransformation or degradation product of ICG is formed in the rat and interferes with the determination of ICG by the spectrophotometric assay. Since the HPLC assay is specific for the parent dye, it is suggested that this assay method be used when determining pharmacokinetic parameters of ICG in rats.

Contribution of metabolites to the route- and time-dependent hepatic effects of di-(2-ethylhexyl)phthalate in the rat.

The effects of exposure to the plasticizer di-(2-ethyl-hexyl)phthalate (DEHP) and its two primary products of presystemic de-esterification, mono-(2-ethylhexyl)phthalate and 2-ethyl-hexanol, on hepatic microsomal oxidation were investigated in rats. The metabolic clearance of antipyrine was utilized as an in vivo measure of the activity of the hepatic microsomal oxidative enzyme system. Subchronic (7 days) p.o. treatment of rats with DEHP, mono-(2-ethylhexyl)phthalate or 2-ethylhexanol produced a substantial increase in both wet liver weight and antipyrine clearance relative to corn oil-treated controls. In contrast, i.p. administration of DEHP resulted in a minor but statistically significant stimulation of liver growth and antipyrine metabolism. Whereas chronic administration of the plasticizer or its metabolites produced apparent induction of hepatic microsomal oxidative enzymes, administration of a single dose of each compound was associated with immediate inhibition of the metabolism of antipyrine. The present data suggest that the products of deesterification of DEHP are primarily responsible for the stimulation of hepatic metabolism observed after long-term exposure to the plasticizer, whereas the parent compound and both metabolites have the potential to produce acute inhibition of hepatic microsomal oxidation in vivo.