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To determine the potential toxicity of prolonged aerosol tobramycin administration, 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks. Prior to, four times during administration and approximately 6 weeks after discontinuation of treatment, we assessed pulmonary function, weight, height, body temperature, eighth cranial nerve function, serum creatinine, blood urea nitrogen, urinary creatinine clearance, plasma iothalamate clearance, urinary beta-2 microglobulin concentration, and Pseudomonas aeruginosa density in sputum. There was no detectable laboratory evidence of nephrotoxicity. Neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction was detected. Pulmonary function tests significantly improved during the first month in all subjects (P less than 0.05) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol. Sputum P. aeruginosa density initially decreased from a mean of 10(7) cfu/gm to a mean of 10(4) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration. However, 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin. We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity. Transient emergence of tobramycin resistant P. aeruginosa may occur.

Tobramycin, an aminoglycoside antibiotic, is used in the treatment of Pseudomonas aeruginosa infections in cystic fibrosis patients. Tobramycin bioactivity, however, is antagonized by sputum. Glycoproteins (mucins) and high-molecular-weight DNA make up 2 to 3% (P. . In vitro, recombinant human DNase (rhDNase) hydrolyzes high-molecular-weight DNA of >50 kb within sputum to fragments of 2 to 4 kb. Studying dialyzable tobramycin, we examined drug binding to whole sputum and to ''mock sputum,'' which consisted of porcine gastric mucin and calf thymus DNA. We also studied the effects of rhDNase treatments of sputum, mock sputum, and calf thymus DNA on tobramycin binding. We found that treatments of sputum, mock sputum, and calf thymus DNA with rhDNase did not significantly increase the tobramycin bioactivity within the dialysates; surprisingly, sputum binding of tobramycin was increased by rhDNase. We conclude that rhDNase does not increase the bioactivity of tobramycin in sputum.LPseudomonas aeruginosa is the most common cause of chronic endobronchial infection in cystic fibrosis (CF) patients; this infection is the major cause of morbidity and mortality in these patients. Tobramycin, an aminoglycoside antibiotic, is used for antipseudomonal chemotherapy in CF patients. In vitro, tobramycin is active against most P. aeruginosa organisms in the absence of sputum; however, in the presence of sputum, tobramycin bioactivity is significantly reduced. Previous investigators have attributed the sputum antagonism of aminoglycoside antibiotics to acidic pH (3, 4, 9), high ionic strength (2,12,14), the presence of divalent cations (2, 7-10, 12, 19, 24), and antibiotic binding to sputum (12,15) or to such sputum components as glycoproteins (18, 20) or DNA (17,18,23).One of the major components of CF sputum is DNA. Highmolecular-weight chromatin DNA is released from leukocytes that accumulate and lyse within purulent sputum (1). In vitro, recombinant human DNase (rhDNase) hydrolyzes the DNA within sputum, and this is associated with a visible reduction of sputum viscosity (22). rhDNase is commercially available for improving lung function in CF patients. During a phase III placebo-control trial, rhDNase treatment improved lung function over a 6-month period (unpublished data). Coadministration of tobramycin by the intravenous or aerosol route with rhDNase may have a potential benefit for CF patients by decreasing the antagonism of tobramycin in CF sputum.We sought to determine if rhDNase treatment of sputum, in vitro, would reduce the antagonism of tobramycin bioactivity by reducing the binding of tobramycin to the high-molecularweight DNA. To determine if the effect of the rhDNase treatment was specific to CF sputum and its major components, we also examined the interaction of tobramycin with ''mock sputum'' (gastric mucin and calf thymus DNA) and with mock sputum that had been treated with rhDNase. MATERIALS AND METHODSReagents. Unless stated otherwise, all chemicals were purchased from Sigma Chemical Company (St. Louis, Mo.)...

We investigated the formation of PGF 2 ␣ 1-ethanolamide, PGE 2 1-ethanolamide, and PGD 2 1-ethanolamide (prostamides F 2 ␣ , E 2 , and D 2 , respectively) in liver, lung, kidney, and small intestine after a single intravenous bolus administration of 50 mg/kg of anandamide to normal and fatty acid amide hydrolase knockout (FAAH ؊ / ؊ ) male mice. One group of three normal mice was not dosed (naïve) while another group of three normal mice received a bolus intravenous injection of 50 mg/kg of anandamide. Three FAAH ؊ / ؊ mice also received an intravenous injection of 50 mg/kg of anandamide. After 30 min, the lung, liver, kidney, and small intestine were harvested and processed by liquid-liquid extraction. The concentrations of prostamide F 2 ␣ , prostamide E 2 , prostamide D 2 , and anandamide were determined by HPLC-tandem mass spectrometry. Prostamide F 2 ␣ was detected in tissues in FAAH ؊ / ؊ mice after administration of anandamide. Concentrations of anandamide, prostamide E 2 , and prostamide D 2 in liver, kidney, lung, and small intestine were much higher in the anandamide-treated FAAH ؊ / ؊ mice than those of the anandamide-treated control mice.This report demonstrates that prostamides, including prostamide F 2 ␣ , were formed in vivo from anandamide, potentially by the cyclooxygenase-2 pathway when the competing FAAH pathway is lacking.

Element 105 / Transition metal group V / Chemical properties / Bromides / Volatility / Gas chromatography AbstractThe retention behavior of volatile bromide molecules of shortlived isotopes of tantalum and element 105 in KCl coated quartz columns was studied using continuous isothermal gas chromatography. HBr and HBr saturated with BBrs vapor were used as reactive gases. The isotopes were produced in the fusion reactions ^°Ne+"" Eu and ^^O + ^^^Bk, respectively. The reaction producta were transported from the accelerator to the chromatography set-up with a gas-jet system using an aerosol with He as carrier gas and KCl as transporting particles. The measured retention times are compared to those of "'Nb bromides from a previous study. The retention times of niobium and tantalum bromides are very similar, in agreement with expectations based on the nearly identical Sublimation enthalpies of NbBrj and TaBr;. For the bromides of element 105, higher retention times are found, indicating a lower volatility of lOSBrs than of NbBrs and TaBrs. On the basis of empirical systematics, a Sublimation enthalpy of 138± 15 kJ/mol can be estimated for 105Br5 from the experimental data.

The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of quinine to its major metabolite, 3-hydroxyquinine. The metabolite contributes approximately 5% of the antimalarial activity of the parent compound in malaria, but up to 10% during convalescence.

We compared the performance of selected ultrasonic and jet nebulizers when aerosolizing several antibiotic formulations to determine optimum combinations for delivery of a respirable antibiotic aerosol. Three ultrasonic devices were tested: the UltraNeb 99/100®, the UltraAIR® and the Aerosonic®. The reusable jet nebulizers were the Dura ProNeb®, Pari‐LL® and the Sidestream®. The six disposable jet nebulizers were Marquest Acorn II®, Hudson T Updraft® II, Baxter MistyNeb®, Pari‐LC®, Pari IS‐2®, and a disposable Sidestream®. Each jet was tested with four compressors: a DeVilbiss AP‐50®, a Pulmo‐Aide®, a DuraNeb® and a PariMaster®. All nebulizing systems were initially tested with normal saline. From the initial data, six jet nebulizers and one ultrasonic device were tested with varying concentrations of tobramycin, gentamicin, ceftazidime, ciprofloxacin and colistin. Output was assessed by measuring volume (milliliters per minute), and amount of drug (milligrams per minute) nebulized. We then measured mean particle size of the antibiotic aerosol with seven jet nebulizers and two different compressors, Pulmo‐Aide® and PariMaster®, and two ultrasonic devices. The rate of nebulization of saline and antibiotic solutions (milliliters per minute) was greater with the ultrasonic device(s) than all jet nebulizer systems tested. Increasing the reservoir antibiotic concentration increased the drug output (milligrams per minute) with the jet nebulizers to a maximum, followed by decreasing output. When antibiotic concentrations were increased the output decreased more precipitously with the ultrasonic devices than with the jet nebulizers. At the highest antibiotic concentrations tested, the ultrasonic devices had the lowest output. Particle size distribution was most dependent on the specific jet device, with particle size distribution less affected by a specific antibiotic or its concentration. Higher reservoir concentrations can be utilized for increasing output of respirable antibiotic aerosols by jet nebulizers. We conclude that antibiotic output is dependent upon both the nebulizing system and the reservoir concentration of antibiotic. Pediatr Pulmonol. 1997; 23:249–260. © 1997 Wiley‐Liss, Inc.