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Clofazimine nanosuspensions were produced by high pressure homogenization and the formulation was optimized for lyophilization. Characterization of the product by photon correlation spectroscopy, laser diffraction and Coulter counter analysis showed that the clofazimine nanosuspensions were suitable for iv injection with a particle size permitting passive targeting to the reticuloendothelial system. Following iv administration to mice of either the nanocrystalline or a control liposomal formulation at a dose of 20 mg clofazimine/kg bodyweight, drug concentrations in livers, spleens and lungs reached comparably high concentrations, well in excess of the MIC for most Mycobacterium avium strains. When C57BL/6 mice were experimentally infected with M. avium strain TMC 724, nanocrystalline clofazimine was as effective as liposomal clofazimine in reducing bacterial loads in the liver, spleen and lungs of infected mice. Nanocrystalline suspensions of poorly soluble drugs such as riminophenazines are easy to prepare and to lyophilize for extended storage and represent a promising new drug formulation for intravenous therapy of mycobacterial infections.

Summary Uric acid concentration and their relationship to different types of hyperlipoproteinemia were investigated in three groups of out-patients. Group A: 273 patients with primary hyperlipoproteinemia without any clinical signs of cardiovascular disease; Group B: 149 patients with a history of myocardial infarction; Group C: 40 patients with primary gout. The results were compared with data derived from randomized healthy persons (employees of the Free University of Berlin).

For a few years now we have regularly reported our progress in the evaluation of possible 3rd generation blowing agents, and we have come to the conclusion that HFC-245fa and HFC-365mfc are the two leading candidates. Previous work included lab scale evaluation of foam samples, measurements of the main relevant physico-chemical characteristics, as well as a thorough evaluation of the chemical stability of HFC-365mfc and HFC-245fa in rigid polyurethane foams [1]. With larger quantities now available from our micropilot plant in Hannover, Germany, we have been able to enlarge our knowledge of HFC-365mfc to allow a sound comparison with the data already available for HFC-245fa.In particular, physico-chemical characteristics have been refined and new ones have been measured; the evaluation of the chronic toxicity of HFC-365mfc is ongoing with first data reported here. Most importantly, additional lab scale tests and large scale trials on industrial lines have been performed to allow an in-depth study of performances in rigid polyurethane foams.This paper completes our previous reports to offer the unique comprehensive comparison of HFC-365mfc and HFC-245fa.

Zusammenfassung Die Gyrasehemmer Norfloxacin, Ciprofloxacin, Pefloxacin und Ofloxacin haben als gemeinsame Grundstruktur das 3-Carboxy-4-oxo-6-fluor-7-(1-piperazinyl)-1,4-dihydrochinolin. Sie durchlaufen verschiedene Biotransformationen, die an Tieren und teilweise auch beim Menschen beschrieben worden sind: 1. Konjugation der Carboxylgruppe mit Glukuronsäure. (Die Bildung des O-Methylesters von Norfloxacin ist nur bei der Ratte gefunden worden). 2. Oxidation des Piperazin-Ringes zur 3-Oxo-Verbindung und Abbau (oder Zerfall) des Piperazin-Ringes über mehrere Zwischenstufen bis zum vollständigen Abbau der Seitenkette. 3. Substitution des in Parastellung nicht besetzten Piperazin-Ringes zum N-Azetyl-bzw. N-Formyl-Derivat (Norfloxacin, Ciprofloxacin). 4. Demethylierung der 4-Methyl-piperazin-Seitenkette (Pefloxacin, Ofloxacin). 5. N-Oxidation der 4-Methyl-piperazin-Seitenkette (Pefloxacin, Ofloxacin). Die Glukuronide sind mikrobiologisch inaktiv. Die Aktivität der Produkte mit modifizierter Piperazin-Seitenkette wechselt von hoch (Oxo-Verbindungen) bis gering (nach Ringspaltung). Quantitative Daten über die Bildung der genannten Metabolite beim Menschen sind zur Zeit noch spärlich. Als Hauptmetabolit wird zumeist das Oxo-Derivat gefunden. Es ist anzunehmen, daß von einigen Substanzen in Zukunft noch weitere Metabolite identifiziert werden.

Cefpodoxime proxetil is a new oral esterified cephem antibiotic with a broad antibacterial spectrum. The dissolution of cefpodoxime proxetil is pH dependent. The objectives of this study were to characterize the pharmacokinetics of cefpodoxime proxetil in two different oral doses and to examine possible interactions with an antacid, aluminum magnesium hydroxide (Maalox 70), and an H2 receptor antagonist, famotidine. Two studies involving the same 10 healthy volunteers were performed. In the first study, cefpodoxime proxetil was administered in two doses, 0.1 and 0.2 g. In the second study, two interventions were performed in a randomized crossover design. For one intervention, the volunteers were pretreated with 40 mg of famotidine 1 h before 0.2 g of cefpodoxime proxetil was administered. In the second trial, participants were given 10 ml of Maalox 70 2 h and 10 ml of Maalox 70 15 min before they received 0.2 g of cefpodoxime proxetil. Serum and urine concentrations were determined by high-performance liquid chromatography. For the statistical evaluation, these data were tested by using the pharmacokinetics of 0.2 g of cefpodoxime proxetil from the first study. The maximum concentrations were 1.19 +/- 0.32 mg/liter after 0.1 g of cefpodoxime proxetil and 2.54 +/- 0.64 mg/liter after 0.2 g of cefpodoxime proxetil. The elimination half-lives were 149 min for 0.1 g and 172 min for 0.2 g of cefpodoxime proxetil. The total increase in the area under the concentration-time curve (AUC) was dose dependent. Combination with Maalox 70 caused a reduction in the AUC from 14.0 +/- 3.9 to 8.44 +/- 1.85 mg.h/liter. After famotidine, the AUC decreased to 8.36 +/- 2.0 mg . h/liter. Corresponding changes were registered for the maximum concentration of drug in serum, 24-h urine recovery, and the time to maximum concentration of drug serum. Cefpodoxime proxetil was well tolerated without any seriously adverse drug reactions.

The pharmacokinetics of cefprozil were determined with 12 volunteers (8 received cefprozil and 4 received a placebo) after oral administration of 500 mg every 12 h over an 8-day period in a randomized, double-blind, placebo-controlled design. Concentrations in serum and urine were measured by high-pressure liquid chromatography and bioassay. The pharmacokinetic parameters were calculated on the basis of an open one-compartment model. The mean maximum concentration in serum on day 1 was 11.5 +/- 2.6 mg/liter, and the time to reach maximum concentration was 122.3 +/- 30 min after administration. Bioavailability parameters (area under the concentration-time curve from zero to infinity, maximum concentration of the drug in serum, and urinary recovery) indicated an excellent absorption. No accumulation over the 8-day period was registered. Cefprozil had a short biological elimination half-life of 58 +/- 10 min and a renal clearance of 210 +/- 51 ml/min, indicating high rates of renal excretion and tubular secretion. Analysis of the fecal flora showed an ecological impact of cefprozil on the intestinal microflora, such as a moderate decrease in enterobacteria and a slight increase in enterococci, staphylococci, and bacteroides during the study. The number of all bacterial species was already normalized 4 days after the administration period. The tolerance of cefprozil proved to be excellent; only a slight and reversible increase of liver enzymes (in two volunteers), mild cephalalgia, tiredness, and soft stool were registered during the 8-day period. Cefprozil had excellent absorption, no accumulation over an 8-day period, and only a limited impact on the intestinal microflora.

FCE 22891 is the oral prodrug of FCE 22101, a new broad-spectrum penem. The pharmacokinetics of FCE 22891 after single-dose administration, its absolute bioavailability, and the effect of food intake on its absorption were investigated in three different randomized crossover studies in healthy volunteers. Drug levels in blood and urine were measured by high-pressure liquid chromatography and bioassay. For optimal comparison of the results of all studies, and since there was good agreement of both methods, only the high-pressure liquid chromatography results are included. The pharmacokinetics of the penem were linear, and its bioavailability after oral administration was 42 +/- 11%. Food intake increased the total area under the curve from 0 h to infinity from 11.9 +/- 3.5 to 14.1 +/- 2.4 mg.h/liter. A specific side effect, i.e., bladder complaints, was registered in some volunteers taking FCE 22891 at doses greater than or equal to 1.0 g.

The pharmacokinetics and serum bactericidal activity of vancomycin alone and in combination with ceftazidime were investigated in 10 healthy volunteers. The pharmacokinetic parameters showed no significant differences (P less than 0.05) between single and combined administration. No antagonistic effects were observed in serum bactericidal activity with the combination against 20 gram-positive and 20 gram-negative locally isolated bacteria. A titer of greater than or equal to 1:8 was generated by the combination against all test strains except enterococci. Seven of ten volunteers developed a typical "red man's syndrome" during the administration of 1.0 g of vancomycin.

In a randomized prospective study, 66 patients with serious bacterial infections--mainly lower respiratory tract infections--were treated with either imipenem plus cilastatin (32 patients) or ciprofloxacin (34 patients); 30 patients in each group were evaluable for efficacy. Substantial underlying disease was present in most of the patients; pathogens isolated prior to treatment (77 isolates) consisted mainly of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and streptococci. Of the etiologic bacteria, 67% were eradicated by ciprofloxacin treatment and 79% by imipenem therapy; however, two patients (6.7%) failed in the ciprofloxacin group, and six patients (20%) did not respond to imipenem treatment (P = 0.25). All patients with therapeutic failures suffered from severe fatal underlying diseases, which had substantial impact on the outcome of treatment. Therapeutic drug monitoring in the ciprofloxacin patients revealed higher concentrations in serum at days 4 and 8 in comparison with day 1 of treatment, indicating that steady-state conditions were reached between days 1 and 4. The total number of side effects was relatively high--eight imipenem patients (25%) and six ciprofloxacin patients (18%) had reactions. Treatment had to be discontinued due to adverse reactions for three ciprofloxacin patients and two imipenem patients. Major side effects in both groups were gastrointestinal and central nervous system-related symptoms. In terms of clinical and bacteriological efficacy and safety, there was no statistical difference between the two groups, and both groups gave good to excellent results for bacterial infections that were difficult to treat.

In 10 volunteers, the pharmacokinetics of ofloxacin [HOE 280, DL 8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3-de] [1,4]benzoxacine-6-carboxylic acid] was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open two- and three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at greater than 0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.

Temocillin concentrations in serum and cerebrospinal fluid (CSF) samples from 8 patients were assayed by high pressure liquid chromatography. It was possible to determine sequential series of ventricular (CSF) and serum concentrations in 4 adult neurosurgical patients with slight to moderate impairment of blood-CSF barriers, because serial CSF samples were obtained from external ventricular drains. In 4 other patients with meningitis, temocillin was given in addition to the regular treatment schedule and 6 ‘spot’ concentrations of temocillin in lumbar CSF and serum samples were determined. Temocillin CSF concentrations in these subjects seemed to be inadequate for the treatment of Gram-positive bacterial meningitis and only partially valuable for the treatment of Gram-negative bacillary meningitis.

Abstract: Objective: In a randomized cross-over study, we assessed pharmacokinetics and intracellular concentrations in polymorphonuclear leukocytes (PMN) and saliva of erythromycin and erythromycylamine, the active metabolite of dirithromycin. Methods: Ten healthy volunteers received 1 g erythromycin b.i.d. or 500 mg dirithromycin qd for 5 days (wash out period, 35 days). Concentrations of erythromycin and erythromycylamine were measured in serum, urine, saliva, and granulocytes by bioassay and high-performance liquid chromatography (HPLC) on days 1, 3, and 5 of each study period, respectively. Results: While maximal serum concentrations (Cmax) and the area under the data (AUDtot) of erythromycin were significantly higher (Cmax 1.44 mg  l−1, AUDtot 5.66 mg  h  l−1) than those of erythromycylamine (Cmax 0.29 mg  l−1, AUDtot 1.96 mg  h  l−1), erythromycylamine had a significantly higher mean residence time (21 h) than erythromycin (5.5 h). Erythromycylamine accumulated significantly more in PMN than erythromycin;␣the accumulation factor of erythromycylamine was 100 with a maximal intracellular concentration of 13.4 mg  l−1, whereas the maximal accumulation factor of erythromycin was 4 with a maximal intracellular concentration of 6.1 mg  l−1. There were no significant differences in maximal saliva concentrations (erythromycin 0.35 mg  l−1, erythromycylamine 0.31 mg  l−1).

The comparative pharmacokinetics of the new oral cephalosporins (ester and nonester types), together with that of the first generation carbacephem, loracarbef, are considered in healthy volunteers. Also in this review, pharmacokinetic and microbiological data are combined in order to predict the possible clinical efficacy of this group of agents. Despite apparent similarities in the structure of these agents, single dose studies have revealed marked differences in the pharmacokinetics of the oral cephalosporins. Multiple dose studies showed no evidence of accumulation with these agents. In the elderly, only minor changes in the pharmacokinetics of the oral agents were observed, and were insufficient to warrant dosage adjustment. Unlike that of the nonester compounds, the bioavailability of the ester cephalosporins is increased when they are administered after food. Variable effects are observed when the ester agents are coadministered with antacids or H2-antagonists; while the absorption of cefetamet pivoxil was unaffected by coadministered antacids or H2-antagonists, the absorption of cefpodoxime proxetil was reduced.

The pharmacokinetic properties of the new quinolones are characterised by a high volume of distribution, long biological half-life, low serum protein binding, elimination mainly by the kidneys, high total and renal clearances, limited biotransformation and a moderate to excellent bioavailability after oral administration. However, each quinolone derivative (ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin) possesses individual pharmacokinetic characteristics, which should be considered in the treatment of patients, especially when liver and/or renal dysfunction exists.

Abstract: A rapid and reliable method for the quantitative determination of cefmenoxime in serum and urine by reversed phase high-performance liquid chromatography is described. Serum was deproteinized with acetonitrile. Urine was diluted with dilute acetic acid (17.5 mmol/l). Separations were performed in isocratic mode using a C18 type column and a precolumn packed with Perisorb RP/8. The eluant consisted of a mixture of acetonitrile and 25.0 mmol/l acetic acid in a ratio of 32/69 (vol/vol). In normal subjects cefmenoxime was well separated from endogenous compounds and various added drugs. Its complete separation was confirmed by selective degradation with beta-lactamase fromBacillus cereus and UV spectrophotometry. The detection limit was 0.3 mg/l at a detection wave-length of 254 nm. Peak areas gave linear results up to concentrations of 500 mg/l. Within-batch precision (coefficient of variation) ranged from 1.1 to 6.2 %. Recovery rates varied from 99.0 to 103.3%. Results of a standard microbiological assay correlated well with those obtained by the present HPLC method. Eight healthy volunteers who were given a single intravenous dose of 1 g cefmenoxime excreted 86.3 ± 5.8 % of the unchanged drug within 24 h in urine.

AbstractAmikacin-loaded liposomes were produced and surface-modified by adsorption of PEG 4000, Tween 80, poloxamer 407 and gelatin. The organ distribution was studied in mice by analysing the amikacin content in liver, spleen, lung, kidneys and serum. Highest serum levels were obtained with the PEG- and Tween 80 modified liposomes (at 2 hours p.inj.). Modification of the liposomes with gelatin as opsonization promoting agent distinctly increased the amikacin concentration in the liver from 36 to 66 mg/kg. Highest spleen concentrations were observed with non-modified and poloxamer 407 liposomes (242 mg/kg and 248 mg/kg, respectively). The data suggest that modification by a simple adsorption process is sufficient to effectively alter the organ distribution. The liposomes differing in organ distribution exhibited also different plasma protein adsorption patterns, up to 115 spots were detected by 2-D PAGE. Hydrophilic albumin was present in a cone, of appr. 80% on liposomes modified with ethoxylated compounds. On the gelatin liposomes, 14% of α-2-Macroglobulin were adsorbed which is a protein typically found on particles rapidly cleared by the RES. IgM, Apo A-I, Apo C-II and α-1-Antitrypsin were other detected proteins.

Die Patientenzahlen, die Zahl der Untersuchungsarten und der Unifang der meisten Untersuchungen vergrossern sich standig. Der Arbeitsablauf wird inimer organisationsaufwendiger und die Berechnungsverfahren komplizierter. Die Zahl und die Qualifikation der Mitarbeiter ist aber begrenzt. Diese Situation macht es erforderlich, dass ein grosser Teil der Arbeiten an eine EDVA ubertragen wird. Dabei ist es aber nicht Anliegen der EDV, die Untersuchungsarten mit geringer Frequenz, selbst bei relativ grossem Arbeitsauftvand, zu erfassen, sondern vor allem die groBe Zahl gleichartiger Untersuchungen und Arbeitsabloufe mit grossem Routineaufwand. Aus diesem Grund wird neben der Messwertverarbeitung besonderer Wert auf organisatorische Probleme des Laborablaufs gelegt.

Ten healthy volunteers received 5 g azlocillin and 2 g moxalactam iv in single and combined administration. Serum and urine concentrations were measured with bioassay and HPLC (high pressure liquid chromatography), and serum bactericidal activity (SBA) was determined at 1 h and 6 h against 6 different clinical isolates. The combined applications of both antibiotics resulted in minor differences in serum kinetics and urine recovery in comparison to single administration. SBAs of both antibiotics against Enterobacteriaceae were between 1 : 4 and 1 : 8.4 for azlocillin and between 1 : 3 and 1 : 8 for moxalactam after 1 h. The combination of both β-lactam antibiotics did not result in a decrease in SBA against any strain; rather all Enterobacteriaceae showed a slight increase of SBA at 1 h. It can be concluded from these results that combination therapy with azlocillin and moxalactam has no adverse influence on the pharmacokinetics or the bactericidal activity of either substance.

7 patients with end-stage renal disease on regular haemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 h for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC.

In an open, randomized, triple crossover study, the effects of cisapride and sucralfate on the pharmacokinetics of sparfloxacin were assessed. Fifteen healthy volunteers received 400 mg of sparfloxacin as a single oral dose on day 0. In a random order, concomitant doses of 10 mg of cisapride three times daily from day -2 to day 2 and 1 g of sucralfate four times daily from day -2 to day 0 were administered. Sparfloxacin concentrations were measured by bioassay and high-performance liquid chromatography. Pharmacokinetic parameters for sparfloxacin alone were as follows (mean +/- standard deviation): maximum concentration of drug in serum (C(max)), 1.27 +/- 0.39 microg/ml; time to C(max) (T(max)), 4.1 +/- 1.9 h; area under the concentration-time curve (AUC), 35.0 +/- 9.7 microg x h/ml; mean residence time, 28.5 +/- 5.7 h; half-life (t1/2), 20 +/- 4 h; urinary recovery (UR x f), 11.0% +/- 2.7%; and metabolite-sparfloxacin ratio in urine, 2.6. For the cisapride group there was a significant decrease in the sparfloxacin T(max) (1.9 +/- 2.1 h) and a significant increase in C(max) (1.74 +/- 0.73 microg/ml). The QTc interval for patients receiving sparfloxacin and cisapride was prolonged by 7.7% compared to the QTc interval during medication-free periods. Significant differences in the values for the group receiving sucralfate compared to the values for the group receiving sparfloxacin alone were found: C(max), 0.77 +/- 0.31 microg/ml; AUC, 18.6 +/- 5.8 microg x h/ml; t1/2, 26 +/- 10 h; and UR x f, 5.8 +/- 1.8%. Concomitant adminstration of cisapride accelerates the absorption and increases the peak concentration of sparfloxacin without having a significant effect on the extent of bioavailability. Coadministration of sucralfate leads to a 44% decrease in the bioavailability of sparfloxacin.

Sparfloxacin, a new fluorinated quinolone, exhibits higher in vitro activity against pneumococci than do ciprofloxacin and ofloxacin. Since up to 30% of cases of pneumococcal pneumonia are associated with bacteremia, and since an increasing percentage of pneumococci are resistant against penicillin, we studied the serum bactericidal activity of sparfloxacin against pneumococci in eight healthy, middle-aged volunteers. Pharmacokinetics in serum and urine after a 400-mg oral dose of sparfloxacin were comparable to those described by other authors. Inhibitory and bactericidal activities in serum were measured for four pneumococcal isolates representing penicillin-susceptible (one isolate), intermediately resistant (two isolates), and highly resistant (one isolate) strains. Geometric mean inhibitory titers ranged between 1:2.4 and 1:6.3 and bactericidal titers ranged between 1:1.3 and 1:3.6 during a time period of 1 to 6 h after drug intake. Although such titers were not sufficient to predict a clinical response based on previous pharmacodynamic studies using quinolone antibiotics, data obtained with volunteers may only partially reflect the clinical situation in which a rise of humoral antibodies directed against pneumococcal antigens may help to reinforce the bactericidal action of the antibiotic.

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

In a randomized, double-blind, placebo-controlled, multiple-dose pharmacokinetic study, the safety and effect on intestinal flora of sparfloxacin (SPX) were determined in 12 healthy male volunteers (8 received SPX and 4 received a placebo). Following fasting and oral administration of 400 mg on day 1 and 200 mg on days 2 to 8, concentrations of the free drug in serum, urine, and feces were measured by high-performance liquid chromatography; serum and urine were also evaluated by a microbiological assay. All results, except those for renal excretion, exclude the glucuroconjugate metabolite. A mean peak concentration in serum (400-mg dose) of 0.56 +/- 0.13 mg/liter was measured 3.52 +/- 0.98 h after administration. Pharmacokinetic parameters (measured by high-performance liquid chromatography) were based on an open, one-compartment model and resulted in the following day 1 (calculated for the 200-mg dose), day 4 (recalculated for a single dose), and day 8 values (mean +/- standard deviation): area under the curve, 16.4 +/- 2.3 (day 1) and 18.3 +/- 5.1 (day 4) mg.h/liter; elimination half-life, 18.3 +/- 3.9 h; steady-state volume of distribution, 4.7 +/- 1.4 (day 1) and 4.3 +/- 1.2 (day 8) liters/kg; apparent total clearance, 201 +/- 31 (day 1) and 190 +/- 51 (day 4) ml/min; renal clearance, 19.1 +/- 5.8 (day 1) and 23.2 +/- 19.4 (day 4) ml/min. Recovery in urine on day 1 was 5.89% +/- 1.4% of the dose in 24 h for the parent compound and 18.4% +/- 6.8% for the SPX glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)

A murine model of bacteremic Haemophilus influenzae type b pneumonia was used to evaluate the therapeutic efficacies of the quinolone antimicrobial agents enoxacin and ofloxacin compared with those of ampicillin and chloramphenicol. Ampicillin-susceptible (AS) and ampicillin-resistant (AR) challenge strains were employed. Treatment with enoxacin or ofloxacin produced intrapulmonary killing of H. influenzae that was superior to that achieved with ampicillin (P less than 0.01 to P less than 0.001 for both AS and AR strains). Ofloxacin and enoxacin also provided killing greater than that with chloramphenicol for the AS strain (P less than 0.01 to P less than 0.001). For the AR strain, ofloxacin provided killing greater than that obtained with chloramphenicol (P less than 0.001). Survival from AS strain pneumonia was 60% in enoxacin-treated and 78% in ofloxacin-treated animals compared with 41% for chloramphenicol-treated and 23% for ampicillin-treated groups. We conclude that enoxacin and ofloxacin may be effective antimicrobial agents in treating either AS or AR strains causing H. influenzae pneumonia.

The pharmacokinetics of apalcillin and piperacillin, each administered intravenously as a single 2-g dose, were compared in 10 volunteers in a randomized study of crossover design using bioassay and high-pressure liquid chromatographic procedures. The concentrations of both penicillins in serum were determined over a period of 12 h and in urine over 24 h. Concentrations of apalcillin and piperacillin at the end of the 15-min infusion were similar; however, at 8 h, concentrations of piperacillin were below measurable levels, whereas concentrations of apalcillin were still measurable at 10 h. Pharmacokinetic parameters were calculated according to a two-compartment open model. The area under the curve and the half-life for apalcillin were larger than for piperacillin. On the other hand, renal clearance of piperacillin was substantially greater than that of apalcillin. Of the apalcillin excreted via the kidneys, approximately one-fifth was eliminated as two microbiologically inactive penicilloic acid derivatives. The nonrenal clearance of apalcillin was 79% of total clearance. Binding of apalcillin to serum protein was almost twice that of piperacillin.

We describe two methods for the quantitative analysis of apalcillin and its metabolites in serum and urine by reverse-phase high-pressure liquid chromatography (HPLC), a fast isocratic method for the parent drug, and a gradient method that allows the simultaneous assay of two metabolites. Serum was deproteinized with acetonitrile, and urine was diluted with buffer solution. The detection limit was about 0.5 micrograms/ml at a detection wavelength of 254 nm and 1.5 micrograms/ml at 310 nm. Within-batch precision (coefficient of variation) varied from 10.2 to 1.1% for concentrations of 7.8 and 185.3 micrograms/ml of serum, respectively. Recovery rates of 95.1 and 97.7% were found in spiked sera. Results obtained by HPLC correlated well with those from a standard microbiological assay (agar diffusion test); the resulting bivariate regression equation for serum was y-bioassay = 2.5 micrograms/ml + 0.992 X xHPLC, and that for urine was ybioassay = 12.0 micrograms/ml + 1.009 X xHPLC. At a detection wavelength of 315 nm, no interferences were observed in 10 healthy volunteers. Healthy subjects who were given 2 g of apalcillin intravenously excreted 18% of the parent drug within 24 h in the urine. Two inactive compounds were furthermore identified in urine as the isomeric forms of the penicilloic acids. Their excretion within 24 h amounted to 6.9 and 11.2% of the dose.

A dose reduction of vancomycin to 1000 mg once a week usually is recommended for haemodialysis patients. Our modified dosing schedule consists of a loading dose of 1000 mg and a maintenance dose of 500 mg administered 3 times a week after haemodialysis. Different vancomycin regimens were retrospectively evaluated by therapeutic drug monitoring and bayesian parameter estimates in 39 dialysis patients. The mean (± SD) trough level in 7 patients receiving only the conventional dosage regimen was significantly lower than in 17 patients strictly treated by the modified schedule (7 ± 4 versus 17 ± 8 mg/L; p = 0.001). The corresponding peaks were low in both groups and no different (23 ± 10 versus 27 ± 12 mg/L). The one week average vancomycin clearance was significantly lower in the conventional dosage group compared to the modified dosage group (6 ± 3 versus 10 ± 3 ml/min; p = 0.001). High-flux dialysers were not used in the conventional dosage group but for 30 percent of the procedures in the modified dosage group, where the vancomycin one week average elimination half-life was 66 hours (± 18) and the volume of distribution 50 litres (± 5). As compared to the bayesian programme, NONMEM calculated comparable pharmacokinetic parameters but could be applied only in 5 cases with a sufficient number of concentration measurements. Ototoxicity occurred in 1 patient, whereas vancomycin treatment was judged as ineffective against infection in 5 of the 39 patients. Their troughs were below 15 mg/L. The apparent tendency toward underdosage can be avoided by giving haemodialysis patients the modified vancomycin schedule (3 × 500 mg/week) with the higher trough levels considered therapeutic (10 - 20 mg/L).

In 12 fasting volunteers, the pharmacokinetics of ciprofloxacin (Bay o 9867; 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carbonic acid) were determined after the administration of 50, 100, and 750 mg orally as well as 50 and 100 mg intravenously over 15 min. Serum and urine concentrations were detected with a bioassay. In addition, urine concentrations after a 50-mg dosing were measured by high-pressure liquid chromatography. The serum course of ciprofloxacin could best be described by an open three-compartment model. High volumes of distribution (exceeding 200 liters/100 kg) suggested effective diffusions in the extravascular space. The terminal half-life of ciprofloxacin ranged between 3 and 4 h. High total and renal clearances suggested additional elimination pathways, such as tubular secretion, metabolism, or biliary excretion. After oral administration, absorption was sufficient, and the absolute bioavailability varied between 0.77 and 0.63. Maximal serum concentrations were attained 0.5 to 1 h after dosing; the higher dosage tended towards a delay in absorption. The proportion of the relative amount of metabolites to the total amount of drug excreted in urine increased from 29.7% after intravenous administration to 42.7% after oral dosing, indicating a first-pass effect of the liver. Ciprofloxacin concentrations with a bioassay were 3 to 27% higher than with high-pressure liquid chromatography, which may indicate the presence of biologically active metabolites. No side effects were recorded.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.

The pharmacokinetics of cefoperazone, cefotaxime, and moxalactam were compared in a cross-over randomized study in 10 healthy volunteers. Each subject received 1.0 g of the three drugs by bolus intravenous injection over 3 min. Serum and urine concentrations were assayed by a microbiological method and in addition by high-pressure liquid chromatography (HPLC) for cefotaxime in five subjects. Maximal concentrations in serum 5 min after the injection were 163 +/- 40.3 mg/liter for cefoperazone, 86.1 +/- 19.0 mg/liter for cefotaxime, and 95.5 +/- 21.1 mg/liter for moxalactam. After 12 h, 1.2 +/- 1.4 mg of cefoperazone per liter and 1.8 +/- 0.9 mg of moxalactam per liter could still be measured. Eight hours after the administration of cefotaxime, serum concentrations were below the detection limit of 0.3 mg/liter in most subjects. By HPLC analysis, the mean maximal concentration of desacetyl cefotaxime was 16.6 +/- 10.5 mg/liter 5 min after application; the metabolite exceeded the serum concentration of the parent compound after 1 to 2 h. Relevant pharmacokinetic parameters were calculated, using two- and three-compartment models. The terminal half-life was 144.1 +/- 37.3 min for cefoperazone, 76.1 +/- 32.0 min for cefotaxime, and 272.4 +/- 114.1 min for moxalactam. The apparent volume of distribution corresponded to the extracellular volume. Only 25.1 +/- 8% of cefoperazone could be detected in urine compared with 53.3 +/- 8.1% of cefotaxime and 61.0 +/- 9.2% of moxalactam in 24 h. A total of 89.6 +/- 11.4% of the cefotaxime dose could be recovered by HPLC in urine, 60.6 +/- 7.7% as cefotaxime and 29.1 +/- 7.0% as desacetyl cefotaxime.

The pharmacokinetics of ciprofloxacin was studied in three groups of healthy volunteers comprising a total of 16 males and 16 females (age 21–35 years; body weight 52–80 kg). Single oral doses of 50, 100, 250, 500 and 750 mg were given to fasting subjects. The 250 mg dose was repeated after a breakfast. Intravenous doses of 50, 100 and 200 mg were given by short infusion in a randomized cross-over sequence. Concentrations of the drug in serum and urine were determined by high-performance liquid chromatography and by a microbiological assay. Mean peak concentrations between 0.37±0.49 mg/l (100 mg dose) and 1.97±0.50 (750 mg dose) were measured 60–75 min after oral administration. Twelve hours after 750 mg ciprofloxacin, serum concentrations were 0.15±0.05 mg/l. Taking a breakfast reduced absorption by 15–20% compared to the fasting state, as judged by peak concentrations, AUC and renal excretion. After 200 mg i. v. (20 min infusion period), initial serum concentrations of 4.0±1.2 mg/l were observed which declined 12 h later to 0.070±0.025 mg/l. Mean cumulated recovery of ciprofloxacin from urine over 24 h varied between 25.5% and 33.6% of oral doses and between 53.2% and 57.4% of intravenous doses. Two of the three metabolites seen in the chromatograms were identified as M1 and M3 (oxo-ciprofloxacin). Cumulated renal excretion after an oral 250 mg dose was 1.2±0.4% of M1 and 5.5±1.6% of M3. Bioavailability of oral doses varied from 0.64±0.16 (100 mg) to 0.52±0.11 (500 mg). The AUC was linearly proportional to a single dose of up to 250 mg. Ciprofloxacin was rapidly absorbed and distributed. High distribution volumes were calculated (mean VDarea 186–217 1). The terminal half-life (t1/2β) was 3.1 to 5.4 h. Mean total body clearance was also high (600 to 693 ml/min · 70 kg)). Tolerance of ciprofloxacin was good for all oral doses and for intravenous administration up to 100 mg per dose. Intravenous infusion of 200 mg ciprofloxacin caused transient local irritation.

The effect of different times of evening administration (2000 hr versus 2200 hr) of sustained-release aminophylline (Euphyllin®®CR) on pharmacokinetics and lung function was investigated in 30 patients presenting with moderately severe asthma. The study protocol followed a randomized three-period change-over design including a placebo period. As the dosing of the investigated SR-formulation is circadian rhythm adapted, the major part of the daily dose, namely 2/3, is affected by the change in time of administration. With regard to the nocturnal peak expiratory flow (PEF), no statistically significant difference between the times of evening administration was detected. However, the concomitant requirement for corticosteroids and inhaled beta-2-mimerics complicates the assessment of the relative clinical efficacy of the major dosing of theophylline during the 24 hr even though this drug is usually not given as a monotherapy in severe patients with reversible airway obstruction.

Ceftazidime and the new SCE-2787 are parenteral cephalosporins with a broad antimicrobial spectrum. Pharmacokinetics, serum bactericidal activities, and side effects were investigated in a randomized crossover study. A total of 12 healthy volunteers received a 20-min infusion of 1.5 g of SCE-2787 or 2.0 g of ceftazidime. Serum and urine concentrations were determined by the bioassay method and by high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) drug concentrations in serum at the end of infusion of SCE-2787 and ceftazidime were 124.4 +/- 23.8 and 233.1 +/- 54.1 mg/liter, respectively. The urine recovery of SCE-2787 was 87.8% +/- 5.5% of dose in 24 h and for ceftazidime was 85.8% +/- 6.3% of dose in 24 h. Metabolites of SCE-2787 could not be detected by HPLC in serum or urine. Pharmacokinetic parameters were calculated both with a noncompartmental analysis and on the basis of an open two-compartment model (drugs are administered into and eliminated from a central compartment only. However, reversible drug distribution from the central space occurs simultaneously into one peripheral space). The area under the concentration time curve from 0 h to infinity of SCE-2787 was 197.9 +/- 25.4 mg.h/liter, and that of ceftazidime was 334.2 +/- 40.0 mg.h/liter. SCE-2787 had a mean terminal half-life in the elimination phase of 109.0 +/- 15.3 min, while that of ceftazidime was 99.0 +/- 13.4 min. The volume of distribution at steady state of SCE-2787 was 17.1 +/- 1.6 liters/70 kg, and that of ceftazidime was 122.9 +/- 1.3 liters/70 kg. The mean residence time of SCE-2787 was 136.4 +/- 15.4 min, and that of ceftazidime was 122.9 +/- 12.7 min. The renal clearance per. 1.73 m2 of SCE-2787 was 103.1 +/- 12.3 ml/min, and that of ceftazidime was 80.6 +/- 13.2 ml/min. The serum bactericidal activities were measured with the microdilution method of Stratton and Reller (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. One hour after administration, we measured mean reciprocal bactericidal titers of SCE-2787 and ceftazidime, respectively, against Escherichia coli of 388 and 243, against Klebsiella pneumoniae of 395 and 138, against Pseudomonas aeruginosa of 13.0 and 12.7, and against Staphylococcus aureus of 32.2 and 4.0. No severe side effects were observed in this single drug administration.

In rats, the effect of a protein-free diet on the maintenance of gestation was investigated during the early postimplantation stages (Days 7 to 10). The growth kinetics of the implantation site, the concentrations of free amino acids in the implantation sites as well as in the maternal liver and the levels of sex hormones in the maternal serum were determined. The results of these studies showed that in the whole implantation site, the absolute amounts of DNA, RNA and nitrogen were significantly lower in the rats fed a protein-free diet compared to the values for rats fed an optimal protein diet. In rats fed a protein-free diet, the concentrations of essential amino acids decreased in the whole implantation site to the same extent as in the maternal liver. In the case of the non-essential amino acids, however, a significant increase in the concentrations of some of the amino acids was observed in the maternal liver. With regard to the essential amino acid pool, it appears that the liver and the decidua can be regarded as being in a dynamic equilibrium.Peripheral prolactin and progesterone concentrations significantly decreased on Day 8 of gestation, while the amounts of LH and total oestrogens remained unchanged.