The aim of the study was to investigate the urinary bactericidal titers (UBTs) and 24 hours area under the UBT versus time curve (AUBT) of intravenuous doripenem (500mg q8h), a new carbapenem, versus intravenous levofloxacin (250mg q 24h) in patients with complicated urinary tract infections (cUTIs) or pyelonephritis. UBTs and AUBTs are pharmacokinetic/pharmacodynamic parameters able to reflect the activity of an antimicrobial substance in the urine. Doripenem and levofloxacin show comparable urinary excretion of approximately 80% and are therefore registered for the treatment of UTI. In order to assess and compare the urinary antimicrobial activity of both substances, UBTs were investigated in 24 patients (10 treated with doripenem and 14 with levofloxacin) for 31 uropathogens and one control strain. Eight strains were tested in all patients and 27 only in the urine of the corresponding patient. Median UBTs (AUBTs) of doripenem for the uropathogens tested ranged between 1.5 and 65,536 (224 and 909,312) and were significantly higher than median UBTs (AUBTs) of levofloxacin ranging between 0 and 128 (0 and 2,208). Eight microbiological failures were observed, three after doripenem treatment and five after levofloxacin treatment. For levofloxacin microbiological failures correlated well with low UBTs and AUBTs, whereas for doripenem there was no correlation. From this study a calculated target attainment rate for levofloxacin predicting therapeutic success in patients with complicated UTI approximated mean UBTs of 100 over 24h or AUBTs of 2,240. Doripenem demonstrated excellent urinary bactericidal activity with the dose administered and appears to be a good alternative in the empiric treatment of cUTI.

Aim: To determine the inhibitory potential of 2 new fluoroquinolones, caderofloxacin and antofloxacin, together with 4 marketed fluoroquinolones, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin, on the activity of cytochrome P450 isoforms 1A2 (CYP1A2) and 2C9 (CYP2C9). Methods: Probe substrates, phenacetin (CYP1A2), and tolbutamide (CYP2C9) were incubated with human liver microsomes and the metabolites were analyzed by liquid chromatography/mass spectrometry using electrospray ionization in positive or negative mode. Glipizide was used as the internal standard in both modes. The inhibitory potential of fluoroquinolones on CYP1A2 and CYP2C9 was investigated. Results: The IC50 values (mumol/L) determined with the cocktail were in agreement with individual probe substrates (alpha-naphthoflavone: 0.27 vs 0.26; sulfaphenazole: 0.49 vs 0.37). Ciprofloxacin showed weak inhibition on both the activity of CYP1A2 (IC50 135 mumol/L) and CYP2C9 (IC50 180 mumol/L), whereas levofloxacin inhibited only CYP2C9 (IC50 210 mumol/L). Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin showed little or no inhibition on the activity of CYP1A2 or CYP2C9 when tested at comparable concentrations (0-200 mg/L). Conclusion: Caderofloxacin, antofloxacin, moxifloxacin, and gatifloxacin are negligible inhibitors to CYP1A2 and CYP2C9. The in vitro system can be used as a high-throughput model to screen similar compounds for the early identification of drug-drug interaction potential.

Percutaneous renal radiofrequency (RF) ablation is a safe and minimally invasive treatment for renal cell carcinoma. The most common minor complications are pain, self-limiting hematuria, and postablation syndrome. Major complications are rare and include significant hemorrhage and thermal injury to the ureter. Reports of infectious complications after ablation are uncommon, but increased risks in patients with ileal conduits have been reported. The present report describes two patients with ileal conduits who underwent percutaneous renal RF ablation and developed infectious complications (a renal abscess and a calyceal-cutaneous fistula) despite prophylactic antibiotic treatment.

Throughout most of the world we are witnessing an ever increasing number of aged people as a percentage of the general population. In the coming years, the unique spectrum of infections presented by an elderly population, particularly those in long-term care facilities, will challenge our ability to maintain an effective battery of antibacterials. The pharmacokinetic parameters of most antibacterial agents are altered when assessed in the elderly due in part to non-pathological physiological changes. The inability to clear a drug from the body due to declining lung, kidney/bladder, gastrointestinal and circulatory efficiency can cause accumulation in the body of drugs given in standard dosages. While this may have the potential benefit of achieving therapeutic concentrations at a lower dose, there is also a heightened risk of attaining toxic drug concentrations and an increased chance of unfavourable interactions with other medications. Pharmacodynamic issues in the elderly are related to problems that arise from treating elderly patients who may have a history of previous antibacterial treatment and exposure to resistant organisms from multiple hospitalisations. Furthermore, the elderly often acquire infections in tandem with other common disease states such as diabetes mellitus and heart disease. Thus, it is essential that optimised dosage strategies be designed specifically for this population using pharmacodynamic principles that take into account the unique circumstances of the elderly. Rational and effective dosage and administration strategies based on pharmacodynamic breakpoints and detailed understanding of the pharmacokinetics of antibacterials in the elderly increase the chances of achieving complete eradication of an infection in a timely manner. In addition, this strategy helps prevent selection of drug-resistant bacteria and minimises the toxic effects of antibacterial therapy in the elderly patient.

Urosepsis accounts for approximately 25% of all sepsis cases and may develop from a community-acquired or nosocomial urinary tract infection (UTI). Nevertheless, the underlying UTI is almost exclusively a complicated one with involvement of the parenchymatous urogenital organs (e.g. kidneys, prostate) and mostly associated with any kind of obstructive uropathy. If urosepsis originates from a nosocomial infection, a broad spectrum of Gram-negative and Gram-positive pathogens have to be expected, which are often multiresistant.In urosepsis, as in other types of sepsis, the severity of sepsis depends mostly upon the host response. The treatment of urosepsis follows the generally accepted rules of the 'Surviving Sepsis' campaign guidelines. Early normalisation of blood pressure and early adequate empirical antibacterial therapy with optimised dosing are equally important to meet the requirements of early goal-directed therapy. In most cases of urosepsis, early control of the infectious focus is possible and as important. Optimal supportive measures need to follow the early phase of resuscitation. To lower mortality from urosepsis, an optimal interdisciplinary approach between intensive care, anti-infective therapy and urology is essential, assisted by easy access to the necessary laboratory and imaging diagnostic procedures.Although most antibacterials achieve high urinary concentrations, there are several unique features of complicated UTI, and thus urosepsis, that influence the activity of antibacterial substances:(i) renal pharmacokinetics differ in unilateral and bilateral renal impairment and in unilateral and bilateral renal obstruction;(ii) variations in pH may influence the activity of certain antibacterials; and (iii) biofilm infection is frequently found under these conditions, which may increase the minimal inhibitory concentrations (MIC) of the antibacterials at the site of infection by several hundred folds. Assessment of antibacterial pharmacodynamic properties in such situations should take into account not only the MIC as determined in vitro and the plasma concentrations of the free (unbound) drug, which are the guiding principles for many infections, but also the actual renal excretion and urinary bactericidal activity of the antibacterial substance. In the treatment of urosepsis, it is important to achieve optimal exposure to antibacterials both in plasma and in the urinary tract. The role of drugs with low renal excretion rates is therefore limited.Since urosepsis quite often originates from catheter-associated UTI and urological interventions, optimal catheter care and optimal strategies to prevent nosocomial UTI may be able to reduce the frequency of urosepsis.

12 volunteers received a single oral dose of 1,000 mg ciprofloxacin XR versus 500 mg levofloxacin to assess urinary bactericidal titers (UBT) against common uropathogens. Areas under UBT-time curves were significantly different for P. mirabilis in favour of ciprofloxacin XR, and for staphylococci in favour of levofloxacin.

High concentrations of levofloxacin in soft tissues and body fluids, including gallbladder and bile, have been repeatedly reported, but no study on its penetration into human liver tissue after single-shot application has yet been published. Levofloxacin 500mg was administered intravenously to 28 patients scheduled for liver resection. Blood samples were taken after the end of infusion and at the time of liver resection; concomitantly, a tissue specimen was also obtained. Serum concentrations (mean+/-standard deviation) 10min after the end of infusion were 6.59+/-1.72mug/mL and decreased only slightly throughout the operation. At the time of liver resection, levofloxacin concentrations in liver tissue were 18.14+/-5.44mug/g with corresponding serum concentrations of 4.84+/-1.37mug/mL. The tissue/serum ratio (3.72+/-0.73 at the time of resection) was nearly constant over the sampling period ranging from 0.4h to 3.8h after the end of infusion, indicating a fast distribution of levofloxacin into the liver tissue. The tissue concentrations showed a significant correlation with serum concentrations and an inverse correlation with the grade of steatosis but not cirrhosis. Infectious post-operative complications were not observed. Levofloxacin penetrates into liver tissue exceptionally well and fast and is therefore a good candidate for antibiotic prophylaxis before invasive hepatobiliary procedures such as liver surgery as well as for treatment of biliary tract infections caused by levofloxacin-susceptible microorganisms.

12 volunteers received a single oral dose of 1,000 mg ciprofloxacin XR versus 500 mg levofloxacin to assess urinary bactericidal titers (UBT) against common uropathogens. Areas under UBT-time curves were significantly different for P. mirabilis in favour of ciprofloxacin XR, and for staphylococci in favour of levofloxacin.

In a randomised crossover study, 14 volunteers received a single oral dose of 500mg levofloxacin or 500mg ciprofloxacin in order to assess plasma concentrations by high-pressure liquid chromatography (up to 24h), urinary excretion and urinary bactericidal titres (UBTs) at intervals up to 120h. The median maximum concentration of levofloxacin in plasma was 6.1mg/L and that of ciprofloxacin was 2.3mg/L. The median cumulative level of renal excretion of the administered dose of the parent drug was 81.2% for levofloxacin and 36.2% for ciprofloxacin. UBTs were determined for a reference strain and nine clinical uropathogens. The median UBTs of both quinolones measured within the first 12h were between 0 and 1:>/=1024, correlating with the minimum inhibitory concentrations (MICs) of the strains. For Gram-negative strains, the UBTs of both quinolones were comparable despite the lower MICs of ciprofloxacin. During further time courses, however, the UBTs of levofloxacin were significantly higher than those of ciprofloxacin. For Gram-positive strains, for which the MICs of levofloxacin were equal to or lower than those of ciprofloxacin, the UBTs of levofloxacin were already significantly higher from the beginning. It can be concluded that overall the doses of the two tested fluoroquinolones may be considered equivalent with regard to treatment of complicated urinary tract infections, although the recommended dosing is twice daily for ciprofloxacin and once daily for levofloxacin.

In a randomized crossover study, 12 volunteers (6 males, 6 females) received a single oral dose of 600 mg of linezolid or 500 mg of ciprofloxacin to assess the concentrations in plasma (up to 24 h), urinary excretion (by high-pressure liquid chromatography), and bactericidal titers in urine (UBT) at intervals up to 120 h. The mean maximum concentration of linezolid in plasma was 13.1 mg/liter, and that of ciprofloxacin was 2.46 mg/liter. The median cumulative levels of renal excretion of the administered dose of the parent drug were 44% for linezolid (range, 28 to 47%; mean +/- standard deviation, 40%+/- 7.8%) and 43% for ciprofloxacin (range, 20 to 56%; mean +/- standard deviation, 40%+/- 9.3%). The UBTs, i.e., the highest twofold dilution (with antibiotic-free urine used as the diluent) of urine that was still bactericidal, were determined for a reference strain and five gram-positive clinical uropathogens for which the MICs of linezolid and ciprofloxacin were as follows: Staphylococcus aureus ATCC 27278, 2 and 0.25 mg/liter, respectively; Staphylococcus aureus (methicillin susceptible), 1 and 16 mg/liter, respectively; Staphylococcus aureus (methicillin resistant), 2 and 64 mg/liter, respectively; Staphylococcus saprophyticus (methicillin susceptible), 1 and 0.25 mg/liter, respectively; Enterococcus faecalis, 2 and 1 mg/liter, respectively; and Enterococcus faecium, 2 and 1 mg/liter, respectively. The median UBTs of linezolid measured within the first 6 h were 1:96 for each of the two enterococcal strains and between 1:128 and 1:256 for the four staphylococcal strains. The median UBTs of ciprofloxacin were 1:64 for the two enterococcal strains; between 1:384 and 1:512 for the two ciprofloxacin-susceptible strains; and 1 (bactericidal activity of undiluted urine only) and 1:2 for the two resistant staphylococcal strains, respectively. The areas under the UBT-time curve (AUBT) for linezolid and ciprofloxacin showed no statistically significant (P < 0.05) differences except for a better AUBT for linezolid for the two ciprofloxacin-resistant staphylococcal strains. For linezolid there were no statistically significant differences in UBTs or AUBTs for ciprofloxacin-susceptible and -resistant strains. Thus, the bactericidal activities of linezolid and ciprofloxacin against susceptible strains in urine were comparable, whereas linezolid also exhibited the same good bactericidal activity against ciprofloxacin-resistant strains. Therefore, linezolid should be tested for use as empirical treatment for complicated urinary tract infections due to gram-positive uropathogens in an appropriate clinical trial.

The aim of the study was to investigate the urinary bactericidal titers (UBTs) and 24 hours area under the UBT versus time curve (AUBT) of intravenuous doripenem (500mg q8h), a new carbapenem, versus intravenous levofloxacin (250mg q 24h) in patients with complicated urinary tract infections (cUTIs) or pyelonephritis. UBTs and AUBTs are pharmacokinetic/pharmacodynamic parameters able to reflect the activity of an antimicrobial substance in the urine. Doripenem and levofloxacin show comparable urinary excretion of approximately 80% and are therefore registered for the treatment of UTI. In order to assess and compare the urinary antimicrobial activity of both substances, UBTs were investigated in 24 patients (10 treated with doripenem and 14 with levofloxacin) for 31 uropathogens and one control strain. Eight strains were tested in all patients and 27 only in the urine of the corresponding patient. Median UBTs (AUBTs) of doripenem for the uropathogens tested ranged between 1.5 and 65,536 (224 and 909,312) and were significantly higher than median UBTs (AUBTs) of levofloxacin ranging between 0 and 128 (0 and 2,208). Eight microbiological failures were observed, three after doripenem treatment and five after levofloxacin treatment. For levofloxacin microbiological failures correlated well with low UBTs and AUBTs, whereas for doripenem there was no correlation. From this study a calculated target attainment rate for levofloxacin predicting therapeutic success in patients with complicated UTI approximated mean UBTs of 100 over 24h or AUBTs of 2,240. Doripenem demonstrated excellent urinary bactericidal activity with the dose administered and appears to be a good alternative in the empiric treatment of cUTI.

Antibiotic resistance nowadays plays an important role in the treatment of uncomplicated and complicated urinary tract infections (UTIs). In uncomplicated UTI efforts are made to use antibiotic substances exclusively for this indication. In complicated UTI substances with activity against bacteria harbouring common resistance mechanisms are investigated. Additionally pharmacokinetic/ pharmacodynamic parameters are used to improve dosing strategies.

Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high- and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae. However, against Pseudomonas aeruginosa, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.

In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400mg) or ciprofloxacin (500mg) to assess urinary bactericidal activity (in eight intervals up to 120h) and pharmacokinetic (PK) parameters (up to 36h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35mg/l and that of ciprofloxacin 2.12mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6h for gatifloxacin were between 1:16 and 1:>/=1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:>/=1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:>/=1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12h showed no difference ([Formula: see text]) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12-24h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120h showed statistically significant ([Formula: see text]) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400mg) would be clinically equivalent to ciprofloxacin (500mg) twice daily-in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)].

The significance and diagnostic value of semen analysis in chronic bacterial prostatitis has been extensively debated and remains controversial. To investigate the diagnostic relevance of semen culture in the bacteriological workup of prostatitis patients, we retrospectively analyzed a clinical database of 696 symptomatic patients. All patients were routinely subjected to a four-glass test, followed by semen culture and analysis. This allowed to dissect from the database three different diagnostic scenarios, and to compare the 'two-glass' pre-/post- massage test and the standard 'four-glass' test with a 'five-glass' test (four-glass plus post-VB3 semen culture). The 'five-glass' test showed 3.6- or 6.5-fold increases in relative sensitivity and lesser reductions (-13.2% or -14.7%) in relative specificity for traditional uropathogens (TUs) compared with the four-glass or two-glass test, respectively. The area under the ROC curve and Jouden's index were increased, whereas positive and negative likelihood ratios were lower than comparators, indicating that the 'five-glass' assay may be superior in confirming the negative outcome of both standard tests. The five-, four-, and two-glass tests detected TUs (Enterobacteriaceae, Enterococci, etc.) in 120, 33, and 20 patients and unusual pathogens (Streptococci, other Gram-positive species, Mycoplasmata, and others) in 130, 56, and 45 patients, respectively. When patients were subjected to pharmacological treatment, including a combination of a fluoroquinolone and a macrolide, no differences in eradication rates were observed between groups diagnosed with different tests, irrespective of pathogen category. Eradication was associated with long-term sign/symptom remission; no significant intergroup differences in sign/symptom scores were observed throughout a 24-month off-therapy follow-up period. In conclusion, our data support the usefulness of semen analysis in the diagnostic workup of prostatitis patients when this test is used to complement the four-glass Meares and Stamey test. Improvement of microbiological assays conveys important diagnostic and therapeutic implications.Asian Journal of Andrology advance online publication. 20 April 2009; doi: 10.1038/aja.2009.5.

Rational antibiotic therapy of urinary tract infections Urinary tract infections (UTI) are frequent infections in the outpatient and nosocomial setting. Generally UTI can be stratified into uncomplicated and complicated infections with respect to treatment options. Uncomplicated UTI are mainly caused by E. coli, whereas complicated UTI exhibit a broader bacterial spectrum with a higher rate of multiresistant uropathogens. On the other hand increasing resistance rates are also found in uncomplicated UTI, e.g. against aminopenicillins, Co-trimoxazol and increasingly also fluoroquinolones. This fact has to be considered in the empirical therapy. Recurrent UTI are frequently found in young, sexually active women, and postmenopausal women. In complicated UTI the complicating factors have to be diagnosed and treated additionally to the antibiotic treatment. If not treated, a severe UTI and urosepsis can develop.

Urosepsis in adults comprises approximately 25% of all sepsis cases and in most cases is due to complicated urinary tract infections (UTIs). In this paper we review the optimal management of urosepsis from the urological point of view. Urosepsis is often due to obstructed uropathy of the upper or lower urinary tract. The treatment of urosepsis comprises four major aspects: Early tissue oxygenation, appropriate initial antibiotic therapy and rapid identification and control of the septic focus in the urinary tract are critical steps in the successful management of a patient with severe urosepsis. To achieve this goal an optimal interdisciplinary approach encompassing the emergency unit, urological specialties and intensive-care medicine is necessary.

The aim of this trial was to compare the efficacy and safety of extended-release ciprofloxacin (CIPRO XR) versus the immediate-release formulation (CIPRO IR) in the treatment of complicated urinary tract infections (UTIs). 212 patients were randomized to CIPRO XR 1,000 mg tablet once daily or CIPROXIN IR 500 mg tablet twice daily. Treatment efficacy was evaluated by bacteriological outcome. Safety was measured by recording adverse events. The rate of bacteriological eradication was 83% in the CIPRO XR group and 75% in the CIPRO IR. the overall incidence of adverse events reported was higher in the CIPRO IR group. The authors conclude that CIPRO XR is a safe and effective treatment for complicated UTIs. Although the limited data available do not consent to support a statistically superior efficacy or safety compared to CIPRO IR, a trend in favor of CIPRO XR is clearly evident in all efficacy and safety variables. CIPRO XR is associated with reduced frequencies of drug-related adverse events compared to CIPRO IR.

The aim of this study was to investigate the feasibility of employing S-carboxymethyl-L-cysteine as a treatment of chronic obstructive pulmonary disease in dogs. To this end the pharmacokinetic parameters of orally administered S-carboxymethyl-L-cysteine were determined in the dog, cow and sheep. Six healthy beagle dogs, six endogenous Greek sheep and four Holstein Fresian calves were orally dosed with 10mg/kg body weight of S-carboxymethyl-L-cysteine. No significant differences in T(max) and T(1/2) were reported between the species. However, significantly higher AUC((0-Last)), 21.56+/-6.67mug hr ml(-1) and AUC(0-infinity), 21.63+/-6.68mug hr ml(-1) were seen in the dogs compared to the sheep and calves. The calculated V(D) was significantly higher in the sheep (10.4+/-2.7Lkg(-1)) and the calves (3.8+/-0.7Lkg(-1)) compared to the dogs (1.0+/-0.6Lkg(-1)). The rank order of increasing C(L) was sheep (3.4+/-2.7L hr(-1) kg(-1))>calves (2.7+/-0.4L hr(-1) kg(-1))>dogs (0.5+/-0.2L hr(-1) kg(-1)). The result for the dogs was significantly lower that the calculated C(L) for the sheep and calves. These results all indicate that the oral administration of S-carboxymethyl-L-cysteine may be useful during the therapeutic management of chronic obstructive pulmonary disease in dogs.

Levofloxacin was recently (May 2008) approved by U.S. Food and Drug Administration as treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg levofloxacin and two studies in 47 healthy adults receiving 500 and 750 mg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and volume of distribution. Consistent with developmental physiology, clearance was also found to be reduced in pediatric patients below 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (AUC0-24,ss, Cmax,ss, and Cmin,ss) following the approved adult dose of 500 mg q.d. The recommended dose of 8 mg/kg b.i.d. was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve comparable efficacy to that of adults.

Isoxsuprine (1-(4-hydroxyphenyl)-2-(1-methyl-2-phenoxyethylamino)-1-propanol, CAS 395-28-8) is a peripheral vasodilator that also stimulates beta-adrenergic receptors. It causes a direct relaxation of vascular and uterine smooth muscles and produces positive inotropic and chronotropic effects. It is widely used to arrest premature labour and miscarriage. The aim of this trial was to investigate the pharmacokinetics of isoxsuprine hydrochloride administered orally to healthy young female volunteers as an extended-release formulation at the doses of 30, 60 and 90 mg compared to 10 mg by i.m. route. A randomised, crossover, four-period, multisequence, single-dose design was adopted. Plasma and urine concentrations of free and total isoxsuprine were evaluated by tandem mass spectrometry that reached a low quantification limit of 1 ng/ml. From plasma concentrations Cmax, tmax, AUC(0-t), AUC(0-infinity), t1/2 and Vd and from urine concentration CUE(0-24h) were evaluated by the non-compartmental model. The free drug was present only in plasma after i.m. route, whereas total isoxsuprine, namely the drug after an enzymatic hydrolysis of the conjugate form, was detected in all plasma and urine samples. The distribution volume of the free drug proved to be 2.5 times higher than that of total isoxsuprine, which indicates a good penetration of the free drug into tissue compartments. Oral absorption was evaluated from the p.o./i.m. percentualized ratio of AUC and CUE and proved to be on average around 51%, being linearly correlated with the three doses administered. The oral absorption proved to be sustained as expected from the zero-order kinetics of the drug release from the core of the extended-release formulation. This has justified different values of half-life that was on average 2.2 h after the i.m. route and around 10 h after the three oral doses. After isoxsuprine administration, both oral and i.m. routes, the heart rate increased from baseline during the 9 h monitoring period. This was an expected finding attributable to the stimulating activity of beta-adrenergic receptors. The tolerability of isoxsuprine proved to be very good with all the four administrations performed.

The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC)(DHA/AS), peak concentration of AS was much higher than that of DHA, with a 2.80- to 4.51-fold ratio of peak concentration (C(max AS/DHA)). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C(max).

BACKGROUND: Levofloxacin is a synthetic fluoroquinolone with a broad spectrum of antibacterial activity. It is indicated for the treatment of respiratory, sinus, skin, and urinary tract infections. Although generic formulations of oral levofloxacin are marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations; these data would be relevant to secure marketing of a test formulation in Mexico. OBJECTIVE: The aim of this study was to compare the bioavailability and determine the bioequivalence of a test formulation (an oral tablet containing levofloxacin 500 mg) with its corresponding listed reference-drug formulation in Mexico (a list issued by Mexican Health Authorities). METHODS: A single-dose, open-label, randomized-sequence, 2-period crossover design was used in this study. Eligible participants were healthy Mexican adults of either sex, randomly assigned to receive the test formulation followed by the corresponding reference formulation, or vice versa, with a 1-week washout period between doses. After a 10-hour overnight fast, the participants received the assigned formulation. Plasma concentrations of levofloxacin were determined using high-performance thin-layer chromatography, and densitometric analysis was performed at 300 nm. For the analysis of pharmacokinetic parameters, including C(max), AUC0(-24), and AUC(0-infinity)), blood samples were drawn at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after administration. The test formulation was considered to meet the criteria for bioequivalence if the geometric mean ratios (test/reference) were with- in the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, vital signs, laboratory analysis, and interviews with participants about adverse events. RESULTS: A total of 26 participants were enrolled, including 14 men and 12 women with a mean (SD) age of 24 (4) years (range, 18-34 years), weight of 62.2 (10.0) kg (range, 45.5-80.0 kg), height of 163 (9) cm (range, 148-176 cm), and body mass index of 23.3 (2.4) kg/m(2)(range, 19.2-27.1 kg/m(2)). The 90% CIs for log-transformed C(max), AUC(0-24), and AUC(0-infinity) were 94.48% to 106.22%, 90.01% to 116.44%, and 85.11% to 114.00%, respectively. Eleven participants reported a total of 20 adverse events during the study. None of the adverse events were considered serious. CONCLUSIONS: In this small study in healthy, fasting Mexican adults, a single 500-mg dose of the test formulation of orally administered levofloxacin met the regulatory requirements to assume bioequivalence based on the rate and extent of absorption. Both formulations were well tolerated.

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2%(90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan Cmax by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR)(90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

A wide range of drugs can cause mental status changes. Fluoroquinolones are one among them and are underrecognised.The CNS side effects of levofloxacin like headache, dizziness, restlessness, tremor, insomnia, hallucinations, convulsions, anxiety and depression are well documented. We report a rare case of middle aged diabetic male admitted to hospital with multiple infections who developed acute psychosis following levofloxacin administration.

Tigecycline exposure (area under the concentration-time curve [AUC((0-infinity))] and maximum serum concentration [C(max)]) and first occurrence of nausea and vomiting were evaluated in 136 healthy subjects after 12.5- to 300-mg single doses. Nausea was more frequent in females (46%, 10/22) compared with males (31%, 11/36) after 100-mg doses. Most nausea (vomiting) events occurred < or =4 h (<6 h) after tigecycline. For doses < or =100 mg, the median duration of nausea and vomiting was approximately 5 h. Based on logistic regression, increased exposure (AUC((0-infinity))>C(max)) to tigecycline results in an increased rate of nausea (P < or =.0001;=.0022) and vomiting (P < or =.0001;=.0006). At the median AUC((0-infinity))(C(max)) for the 50-mg dose group, the probability of nausea and vomiting was 0.26 (0.29) and 0.07 (0.11), respectively. Model-predicted rates of nausea and vomiting were comparable with those observed for the tetracycline class of antibiotics, with tolerable rates predicted after 50-mg doses of tigecycline.