A population pharmacokinetic analysis of the penetration of the prostate by levofloxacin.

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of the Enterobacteriaceae, particularly Escherichia coli, play a central role, while intracellular pathogens such as Chlamydia are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.

Photoreaction potential of orally administered levofloxacin in healthy subjects.

OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a single-center, double-blind, randomized study, 30 adults (20 men, 10 women) received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline photoexposure prior to drug administration, each subject was exposed to UVB light at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25 J/cm2). Photoexposure was repeated on day 5, two hours following final drug administration, and response was determined using both a photoreaction rating scale and investigator assessment. RESULTS: Using the photoreaction rating scale, following UVB exposure on day 5, no abnormal photoreactions were observed among levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of 24 levofloxacin-treated and three of six placebo-treated subjects, with no associated symptoms. By investigator assessment, all subjects had a negative reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal reactions were mild and similar for both treatment groups. No subject experienced an immediate wheal-and-flare reaction. There were no statistically significant differences between treatment groups for any of the comparisons. CONCLUSIONS: Levofloxacin has a low photosensitizing potential when administered to healthy subjects.

Heterohybridomas that secrete high levels of pseudomonas-specific therapeutic human monoclonal antibodies: their generation and large scale growth in an automated hollow fiber cell culture system.

Fusion of lymphoblastoid cell lines that produce human monoclonal antibodies against Pseudomonas aeruginosa with the human/mouse heteromyeloma SHM-D33 generated heterohybrids that were stable and secreted antibody in the range of 20 to 300 micrograms/ml. One of the hybridoma cell lines ws adapted to serum-free medium and maintained for 60 days in an automated hollow fiber system. During that time, 3 g of antibody was produced. Such yields make it possible to evaluate these monoclonals for their therapeutic potential in patients at risk for Pseudomonas infections.

Site of binding of IgG2b and IgG2a by mouse macrophage Fc receptors by using cyanogen bromide fragments.

Cyanogen bromide fragments of murine IgG2b and IgG2a immunoglobulins were used to localize the sequences that are bound by specific IgG2b and IgG2a Fc receptors on murine macrophages. One fragment from the CH2 domain of IgG2b bound to the gamma 2b Fc receptor. Two fragments from IgG2a--one one from the CH2 domain, differing by only four amino acids from the homologous IgG2b fragment, and the other from the CH3 domain--specifically bound to the gamma 2a Fc receptor. In both a rosetting assay and a radioactive binding assay, these two fragments from IgG2a competed with intact IgG2a: however, they did not compete with each other. Rather, binding of the fragment from the CH3 domain of IgG2a augmented the binding of the fragment from the CH2 domain of IgG2a but not that of the homologous fragment from IgG2b. The binding of both IgG2a fragments was abolished by trypsin treatment of macrophages. These data suggest that 1) a sequence in the CH2 domain of IgG2b is sufficient for binding to the gamma 2b Fc receptor, 2) sequences from both the CH2 and CH3 domains of IgG2a bind to the gamma 2a Fc receptor, and 3) the binding of sequences from the CH3 domain of IgG2a may induce a conformational change in the gamma 2a Fc receptor that leads to enhanced binding of sequences from the CH2 domain.