Efficacy of liposome-encapsulated ciprofloxacin in a murine model of Q fever.

Encapsulation of antibiotics may improve treatment of intracellular infections by prolonging antibiotic release and improving antibiotic uptake into cells. In this study, liposome-encapsulated ciprofloxacin for inhalation (CFI) was evaluated as a postexposure therapeutic for the treatment of Coxiella burnetii, the causative agent of Q fever. Intranasal treatment of male A/Jola (A/J) mice with CFI (50 mg/kg of body weight) once daily for 7 days protected mice against weight loss and clinical signs following an aerosol challenge with C. burnetii. In comparison, mice treated twice daily with oral ciprofloxacin or doxycycline (50 mg/kg) or phosphate-buffered saline (PBS) lost 15 to 20% body weight and exhibited ruffled fur, arched backs, and dehydration. Mice were culled at day 14 postchallenge. The weights and bacterial burdens of organs were determined. Mice treated with CFI exhibited reduced splenomegaly and reduced bacterial numbers in the lungs and spleen compared to mice treated with oral ciprofloxacin or doxycycline. When a single dose of CFI was administered, it provided better protection against body weight loss than 7 days of treatment with oral doxycycline, the current antibiotic of choice to treat Q fever. These data suggest that CFI has potential as a superior antibiotic to treat Q fever.

Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

Anatomic localization of 24- and 96-h particle retention in canine airways.

Long-term retention of particles in airways is controversial. However, precise anatomic localization of the particles is not possible in people. In this study the anatomic location of retained particles after shallow bolus inhalation was determined in anesthetized, ventilated beagle dogs. Fifty 30-cm(3) boluses containing monodisperse 2.5-micron polystyrene particles (PSL) were delivered to a shallow lung depth of 81-129 cm(3). At 96 h before euthanasia, red fluorescent PSL were used; at 24 h, green fluorescent PSL and (99m)Tc-labeled PSL were used. Clearance of (99m)Tc-PSL was measured during the next 24 h. Sites of particle retention were determined in systematic, volume-weighted random samples of microwave-fixed lung tissue. Precise particle localization and distribution was analyzed by using gamma counting, conventional fluorescence microscopy, and confocal microscopy. Within 24 h after shallow bolus inhalation, 50-95% of the deposited (99m)Tc-PSL were cleared, but the remaining fraction was cleared slowly in all dogs, similar to previous human results. The three-dimensional deposition patterns showed particles across the entire cross-sectional plane of the lungs at the level of the carina. In these locations, 33 +/- 9.9% of the retained particles were found in small, nonrespiratory airways (0.3- to 1-mm diameter) and 49 +/- 10% of the particles in alveoli; the remaining fraction was found in larger airways. After 96 h, a similar pattern was found. These findings suggest that long-term retention in airways is at the bronchiolar level.

Aerosol bolus dispersion and aerosol-derived airway morphometry: assessment of lung pathology and response to therapy, Part 1.

review discusses the potential utility of two methods using inhaled aerosols to detect and diagnose lung disease and to evaluate the efficacy of therapy. Aerosol bolus dispersion measures convective gas mixing; aerosol-derived airway morphometry assesses the calibers of airway and airspaces. These two methods are discussed in terms of their ease of use (simplicity and acceptability) and current data regarding their validity, reproducibility, specificity, sensitivity, and detection of lung improvement with therapy. Part 1 of this review focuses upon aerosol bolus dispersion; Part 2(1) focuses upon aerosol-derived airway morphometry. Aerosol bolus dispersion has many features that make it clinically attractive. It is simple to administer and patients can successfully perform the maneuvers. It detects known alterations in the lungs. It is reproducible and has high specificity and sensitivity. However, every lung disease or condition known to be detected by aerosol bolus dispersion is also detected by spirometery, maximal expiratory flow-volume curves, or another conventional lung function test. This, aerosol bolus dispersion appears best reserved as a specialized method to supplement conventional lung function tests and to characterize convective gas transport.

Spirometry--acceptability and reproducibility in spinal cord injured subjects.

The American Thoracic Society (ATS) has formulated guidelines for spirometry. We hypothesized that individuals with SCI (SCI), as a result of weak respiratory muscles, would exhibit poor test acceptability and reproducibility. Seventy-eight SCI subjects (39 with complete SCI) answered a respiratory questionnaire and performed spirometry. Of those with complete SCI, the proportion of subjects which met ATS criteria decreased with higher levels of injury. Poor test performance was not associated with age, respiratory symptoms or muscle fatigue. The most common reason for failing to meet ATS criteria for acceptability was excessive back extrapolated volumes (EBEV). Individuals with efforts that were acceptable except for EBEV and/or for exhalation of less than six seconds had values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) that were reproducible. If ATS criteria for acceptable spirometry were used in studying subjects with SCI, individuals producing otherwise reproducible values for FVC and FEV1 would be excluded. We found reproducibility similar to what has been reported in other cohorts and conclude that longitudinal study of respiratory function in SCI is feasible.

Aerosol bolus dispersion and convective mixing in human and dog lungs and physical models.

The dispersion of aerosol boluses in the lung is a probe for convective mixing and has been proposed as a marker for abnormal lung function. To better understand the factors underlying this phenomenon, aerosol dispersion was compared in human subjects, dogs, and various physical models. In all systems, dispersion increased with the volumetric penetration of the aerosol bolus. The rate of this increase was 83% greater in humans compared with dogs. Dispersion in dogs was close to that in a packed bed with beads of 2.5 mm. Aerosol dispersion decreased with increasing flow rate in human subjects. An artificial larynx inserted into the straight tube caused a 33% increase in dispersion. In humans, aerosol dispersion was significantly correlated with forced expired flow between 25 and 75% of vital capacity. A 2-s pause between inspiration and expiration increased dispersion 23-58% in three isolated dog lungs but did not affect dispersion in the packed bed. The data suggest that lung geometry, flow rate, particle mobility, and the larynx all significantly affect aerosol dispersion by influencing the reversibility of aerosol transport between inspiration and expiration.

Aerosol-derived lung morphometry: comparisons with a lung model and lung function indexes.

This study evaluated the ability of aerosol-derived lung morphometry to noninvasively probe airway and acinar dimensions. Effective air-space diameters (EAD) were calculated from the time-dependent gravitational losses of 1-microns particles from inhaled aerosol boluses during breath holding. In 17 males [33 +/- 7 (SD) yr] the relationship between EAD and volumetric penetration of the bolus into the lungs (Vp) could be expressed by the linear power-law function, log (EAD) alpha beta log (Vp). Our EAD values were consistent with Weibel's symmetric lung model A for small airways and more distal air spaces. As lung volume increased from 57 to 87% of total lung capacity (TLC), EAD at Vp of 160 and 550 cm3 increased 70 and 41%, respectively. At 57% TLC, log (EAD) at 160 cm3 was significantly correlated with airway resistance (r = -0.57, P less than 0.0204) but not with forced expired flow between 25 and 75% of vital capacity. Log (EAD) at 400 cm3 was correlated with deposition of 1-micron particles (r = -0.73, P less than 0.0009). We conclude that aerosol-derived lung morphometry is a responsive noninvasive probe of peripheral air-space diameters.

Intersubject variability in particle deposition does not explain variability in responsiveness to methacholine.

How variable is the deposition of inhaled methacholine (MCH) in the respiratory tract during a challenge test? Does this variability contribute to the variability of airway responsiveness? To examine these questions we estimated the deposition of polydisperse MCH droplets by measuring the deposition of surrogate diethylhexyl sebacate (DEHS) droplets that were similar in size (1.5 microns) but monodisperse. Light scattering photometry and flow measurements were used to compute inspired and expired DEHS particle number. Deposition of DEHS during 4 breaths was measured twice at baseline and after every dose of MCH during an abbreviated challenge test in 16 subjects. Deposition was then compared with reactivity. Reactivity to MCH was expressed as the dose-response slope; it was calculated as percent final change in FEV1/cumulative dose MCH inhaled. Dose-response slopes ranged from zero (nonreactive) to -15.0 (very reactive) %/mumol (mean -3.2 +/- 5.3 SD). Seven subjects had a 20% or greater decrement in FEV1 after their highest MCH dose. Baseline DEHS deposition, which ranged from 66 to 84% (mean 77 +/- 5 SD), was not significantly different between responders and nonresponders and was not a significant predictor of the dose-response slope. Reactivity was significantly associated with an increase in deposition produced by MCH (p less than 0.007). This increase was small, however (relative change less than 7%), so that the effect on the deposited dose of MCH was minimal. We conclude that, with the breathing pattern used, individual differences in DEHS (and MCH) deposition were small and contributed little to intersubject variability of responsiveness to inhaled MCH.

Effect of cystic fibrosis on inhaled aerosol boluses.

An aerosol bolus undergoes changes in shape between its inspiration and expiration. In comparison with the inhaled bolus, the exhaled bolus is more spread because of convective mixing, may have a shift in the location of the mode caused by asymmetries of filling and emptying of lung units, and contains fewer particles because of particle deposition. We hypothesized that the extent of these changes is related to lung health. To examine this, 11 patients with cystic fibrosis (CF) and 11 healthy subjects inhaled 70 cm3 boluses containing 1 micron monodisperse particles that were inspired to volumetric penetrations (Vp) of 100 to 700 cm3. As each bolus was expired, we measured spreading (volumetric width at one-half aerosol concentration peak height), modal shift, and particle deposition. Patients with CF exhaled boluses that were broader than those exhaled by normal subjects at all penetrations examined. At a Vp of 600 cm3, patients had a mean bolus half-width that was 68% greater than that of healthy subjects (p less than 0.0001), and they exhaled the bolus mode 20% earlier (p less than 0.0002). Particle deposition was increased compared with that in normal subjects at all Vp. For example, mean deposition at a Vp of 600 cm3 was 46.2 +/- 2.6% (SE) for the patients versus 25.8 +/- 1.6% for the normal subjects (p less than 0.0001). Among the patients with CF, pulmonary function parameters indicating obstruction were significantly correlated with bolus spreading and aerosol deposition: the percent predicted FEV1/FVC was inversely correlated with spreading (r = -0.88, p less than 0.0004) and deposition (r = -0.84, p less than 0.0008).(ABSTRACT TRUNCATED AT 250 WORDS)

Convective mixing in human respiratory tract: estimates with aerosol boli.

Convective gas mixing in the respiratory tract of 17 healthy male subjects was studied by an aerosol bolus technique. The monodisperse 1 micron di(2-ethylhexyl)sebacate droplets we used behaved as a nondiffusing gas. As the bolus was inspired to different depths and then expired, we measured the extent to which the bolus spread. We found that the deeper the bolus penetrated into the lungs, the more it became dispersed. The half-width of the expired bolus was a linear function of the volume to which the bolus penetrated at volumetric penetrations of 100-800 cm3. This suggests that convective mixing is not confined to central airways but can also occur in the lung periphery.

Total deposition of ultrafine sodium chloride particles in human lungs.

The total deposition of monodisperse, 0.026-0.19 micron (dry volume equivalent diameter) sodium chloride particles in the lungs of five healthy subjects, who breathed orally, was measured. For a tidal volume of 1,000 ml and flow rate of 500 ml/s, the percentages deposited were: 37.2 +/- 8.4% (mean +/- SD) for 0.026 micron, 23.8 +/- 3.3% for 0.051 micron, 22.8 +/- 3.1% for 0.096 micron, and 31.8 +/- 6.2% for 0.19 micron particles. The deposition minimum corresponded to a particle size of approximately 0.08 micron. Deposition did not correlate with measures of lung volume or body size but did correlate with forced expired flow rate after 75% of forced vital capacity (FVC) exhaled (FEF 75%/FVC) and with percent-predicted values for FEF 25-75% and FEF 75%. Lengthening the breathing period from 4 to 8 s/breath while maintaining flow rate at 500 ml/s caused an additional 11.3 +/- 3.1% of the inhaled particles to deposit. Sedimentation and diffusion were found to be the principal deposition mechanisms. These hygroscopic particles deposited according to sizes they would attain in air with a relative humidity between 96 and 100%.

Assessing the work environment for agents that may cause occupational pulmonary disease.

The industrial hygienist is a professional trained in the resognition, evaluation, and control of environmental stresses in the workplace and as such serves as a valuable recourse for medical personnel concerned with occupational lung disease. Knowledge of the precise identity and quantity of workplace hazards is often essential in diagnosing occupational lung disorders. In addition, an industrial hygienist familiar with the process can assess whether there is a likelihood of exposure to levels above the limits which are considered to be safe. This valuable industrial hygiene information can be from government (e.g., OSHA, state agencies), universities or consulting firms.

A psychological autopsy of an indian adolescent suicide with implications for community services.

This psychological autopsy of the suicidal death of an adolescent Indian boy includes a brief family background, a history of his difficulties, and a report of his psychological evaluation. There is an attempt to understand the societal and familial factors that seem to have prediposed him to commit suicide. The report includes an analysis of the resources currently available in Indian communities and a recommendation for the kinds of resources that might prevent suicide in this setting.

Caring for the patient with breast cancer.

The management of the patient with cancer of the breast is a challenge to the family physician. Foremost is the need to educate the patient about self-examination and the physician's role in providing a thorough clinical evaluation and the appropriate use of mammography. Once a diagnosis is established the patient requires counselling and referral to the needed specialists. Finally, the family physician is in a key position to coordinate the necessary services, provide access to rehabilitation programs and offer the necessary psychological support to the patient and her family.