A regulatory hydrophobic area in the flexible joint region of plasminogen activator inhibitor-1, defined with fluorescent activity-neutralizing ligands. Ligand-induced serpin polymerization.

We have characterized the neutralization of the inhibitory activity of the serpin plasminogen activator inhibitor-1 (PAI-1) by a number of structurally distinct organochemicals, including compounds with environment-sensitive spectroscopic properties. In contrast to latent and reactive center-cleaved PAI-1 and PAI-1 in complex with urokinase-type plasminogen activator (uPA), active PAI-1 strongly increased the fluorescence of the PAI-1-neutralizing compounds 1-anilinonaphthalene-8-sulfonic acid and 4,4'-dianilino-1,1'-bisnaphthyl-5,5'-disulfonic acid. The fluorescence increase could be competed by all tested nonfluorescent neutralizers, indicating that all neutralizers bind to a common hydrophobic area preferentially accessible in active PAI-1. Activity neutralization proceeded through two consecutive steps as follows: first step is conversion to forms displaying substrate behavior toward uPA, and second step is to forms inert to uPA. With some neutralizers, the second step was associated with PAI-1 polymerization. Vitronectin reduced the susceptibility to the neutralizers. Changes in sensitivity to activity neutralization by point mutations were compatible with the various neutralizers having overlapping, but not identical, binding sites in the region around alpha-helices D and E and beta-strand 1A, known to act as a flexible joint when beta-sheet A opens and the reactive center loop inserts as beta-strand 4A during reaction with target proteinases. The defined binding area may be a target for development of compounds for neutralizing PAI-1 in cancer and cardiovascular diseases.

Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes.

OBJECTIVE: To determine the safety and efficacy of ofloxacin otic solution in the treatment of acute otorrhea in children with tympanostomy tubes. DESIGN: Multicenter study with an open-label, prospective ofloxacin arm and retrospective historical and current practice arms. SETTING: Ear, nose, and throat pediatric and general practice clinics and office-based practices. SUBJECTS: Children younger than 12 years with acute purulent otorrhea of presumed bacterial origin and tympanostomy tubes. INTERVENTION: Instillation of 0.3% ofloxacin, 0.25 mL, twice daily for 10 days in the prospective arm; review of medical records in the retrospective arms. MAIN OUTCOME MEASURES: The primary index of clinical efficacy was absence (cure) or presence (failure) of otorrhea at 10 to 14 days after therapy. The primary index of microbiologic efficacy (in the ofloxacin arm only) was eradication of pathogens isolated at baseline. Safety was evaluated in the ofloxacin arm only. RESULTS: Significantly more clinically evaluable ofloxacin-treated subjects were cured (84.4%; 119/141) than were historical practice subjects (64.2%; 140/218) (P< or =.001) or current practice subjects (70%; 33/47) (P< or =.03). All baseline pathogens were eradicated in 103 (96.3%) of 107 microbiologically evaluable ofloxacin subjects. Adverse events considered "possibly" or "probably" treatment related occurred in 29 (12.8%) of 226 ofloxacin-treated subjects. CONCLUSION: Ofloxacin is safe and significantly more effective than treatments used in historical or current practice for acute purulent otorrhea in children with tympanostomy tubes.

Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes.

Acute otitis media (AOM) in children with tympanostomy tubes in place typically presents with otorrhea (draining ear). Because therapy is not standardized, various topical and systemic antibiotics of unproven efficacy and safety have been used in this indication. This study compared the safety and efficacy of ofloxacin otic solution, 0.3% (OFLX) with that of Augmentin oral suspension (AUG) in pediatric subjects 1-12 years of age with tympanostomy tubes and acute purulent otorrhea. Subjects were randomized to receive 10d of OFLX, 0.25 ml topically bid, or of AUG, 40 mg/kg per day. Audiometry was performed in subjects > or =4 years of age. Overall cure rate for clinically evaluable subjects was 76% with OFLX (n = 140) and 69% with AUG (n = 146; P = 0.169). Overall eradication rates for OFLX and AUG were similar for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis and were superior with OFLX for Staphylococcus aureus and Pseudomonas aeruginosa (P<0.05 for both). OFLX had a greater overall pathogen eradication rate (96% vs. 67%; P<0.001). Treatment-related adverse event rates were 31% for AUG and 6% for OFLX (P<0.001). Neither treatment significantly altered hearing acuity. Topical ofloxacin 0.3% otic solution 0.25 ml bid was as effective and better tolerated than systemic therapy with Augmentin oral suspension 40 mg/kg per day in treating AOM in children with tympanostomy tubes.

Cefaclor vs amoxicillin in the treatment of acute, recurrent, and chronic sinusitis.

BACKGROUND: The treatment of acute, recurrent, and chronic sinusitis remains controversial because of the presence of a wide variety of aerobic and anaerobic bacteria in the sinuses. DESIGN: This double-blind, randomized trial compared cefaclor with amoxicillin in the treatment of acute, recurrent, and chronic maxillary sinusitis using clinical evaluation, roentgenography, and microbiologic evaluation of antral aspirates. SETTING: Outpatient office of five otorhinolaryngologists in Salt Lake City, Utah. PATIENTS: One hundred eight adult patients with acute, recurrent, or chronic maxillary sinusitis. INTERVENTION: Oral treatment with cefaclor (500 mg) twice daily or amoxicillin (500 mg) three times daily for 10 days. MAIN OUTCOME MEASURE: Clinical response to treatment with cefaclor vs amoxicillin. RESULTS: Fifty-six patients with acute sinusitis, 25 with recurrent sinusitis, and 15 with chronic sinusitis were evaluable. Although multiple organisms were common in each group, patients with acute sinusitis were more likely to have Haemophilus influenzae or Streptococcus pneumoniae, and patients with recurrent or chronic sinusitis were more likely to have anaerobes in sinus aspirate. Whether treated with cefaclor or amoxicillin, clinical improvement occurred in 86% of patients with acute sinusitis and 56% of patients with recurrent sinusitis. Patients with chronic sinusitis were too few to allow statistical analysis of the differences in outcome between them and patients with recurrent or acute sinusitis. Resistance of the cultured organisms to the study drug used was unrelated to treatment outcome. CONCLUSIONS: The rate of clinical improvement was high in patients with acute sinusitis but was less favorable in those with recurrent and chronic disease regardless of the study drug used. The susceptibility of organisms isolated to the study drugs was unrelated to outcome.

Acute bacterial maxillary sinusitis: results of U.S. and European comparative therapy trials.

Loracarbef, which is the first agent of the carbacephem class of beta-lactam antibiotics to be developed, provides good activity against a broad spectrum of bacteria. A single-blinded, randomized, parallel clinical trial in 10 centers in the United States compared the efficacy and safety of loracarbef with that of amoxicillin/clavulanate potassium in the treatment of acute bacterial maxillary sinusitis. A 7-10-day regimen of loracarbef (400 mg twice daily) was as effective as amoxicillin/clavulanate (500/125 mg three times a day) and resulted in somewhat fewer side effects. The results of a European trial in Sweden, Finland, and Iceland showed that loracarbef was clinically more effective than doxycycline in the treatment of acute bacterial maxillary sinusitis.

Loracarbef (LY 163892) vs amoxicillin/clavulanate in bacterial maxillary sinusitis.

Loracarbef (LY 163892), a beta-lactam antibiotic (carbacephem), was compared with amoxicillin/clavulanate potassium in a 10-day, single-blind, randomized parallel trial in the treatment of acute bacterial maxillary sinusitis. Based on posttherapy aspirate and culture, there was a 95.2% bacteriologic cure rate in patients receiving loracarbef (400 mg twice daily) and an 86.7% cure rate in patients receiving amoxicillin/clavulanate (500/125 mg three times daily) (p = 0.359). Loracarbef was comparable in efficacy to amoxicillin/clavulanate with a more desirable safety profile.

Skin flap survival. Influence of infection, anemia, and tubing.

The use of regional skin flaps in reconstructive head and neck surgery is well established. The specific factors that influence the survival of the various skin flaps are numerous. An experimental approach to this problem has been outlined and carried out. Rabbits were used to evaluate the effect of severe anemia on pedicle skin flap survival. Infected as well as noninfected flaps were studied. Skin flaps of various length-to-width ratios were placed on the backs of each rabbit. These flaps included the full-thickness skin and the panniculus carnosus. Some animals were infected with pure cultures of Staphylococcus aureus and Pseudomonas aeruginosa. Some animals were made anemic by slowly bleeding them until the desired hematocrit leading was achieved. The best flap survivals occurred in the noninfected, anemic group. The next best survival percentage was noted in the noninfected group with normal hematocrit readings. The poorest survival was noted in rabbits with a normal hematocrit reading and infection. In all groups, flattened pedicled grafts had better survival than tubed pedicled grafts.