A comparison of the availability of tobramycin for inhalation from vented vs unvented nebulizers.

STUDY OBJECTIVE: To compare drug output from a vented nebulizer (Pari LC Jet Plus) with a traditional unvented nebulizer (Hudson 1730 T Up-Draft 11) using aerosolized tobramycin, which is frequently used in the treatment of cystic fibrosis. DESIGN: Six nebulizers of each type were filled with a 4 mL tobramycin (80 mg) solution and were driven by a compressor (Pulmo-Aide). Various inspiratory flows (VI) (0, 5, 10, 15, 20 L/min for the Pari LC Jet Plus and 0, 5, and 10 L/min for the Hudson 1730, all at 40% relative humidity) were directed through each nebulizer. Drug output was measured from changes in weight and concentration (assessed by changes in osmometry) within the nebulizer. Particle size distributions were determined by laser diffraction allowing the calculation of the amount of aerosol output in the respirable range (<5 microm). The nebulizers were first run until end-nebulization to establish total drug output and then for either 4 or 5 min to determine the rate of drug output (mg/min) before intermittent aerosol output. RESULTS: The total drug output without VI for both the unvented and the vented nebulizers was not significantly different, 55 (51, 60) mg for the Hudson 1730 vs 51 (49, 53) mg for the Pari LC Jet Plus (mean [95% confidence limits]). Inspiratory flow had no effect on the unvented Hudson 1730 nebulizer but significantly increased the rate of total drug output and the rate of drug output in the respirable range for the vented Pari LC Jet Plus nebulizer (VI=0, 3.35 [2.84, 3.85] and 1.72 [1.48, 1.96] compared with VI=20, 9.87 [9.03, 10.70] and 6.11 [5.33, 6.88] mg/min). CONCLUSIONS: These findings indicate that the increase in the rate of drug output with VI for the vented nebulizer would result in shorter nebulization times and a relative decrease in drug loss during the expiratory phase.

A comparison of pulmonary availability between Ventolin (albuterol) nebules and Ventolin (albuterol) Respirator Solution.

The two most common albuterol preparations used for nebulization are: (1) Ventolin (albuterol) respirator solution (Glaxo Canada Inc; Montreal, Canada) of which 2.5 mg (0.5 mL) is diluted with 2 mL of normal saline solution, and (2) the preservative-free, prediluted Ventolin (albuterol) Nebules PF (Glaxo) (2.5 mg/2.5 mL). The two preparations were compared using both a Hudson 1720 "T" up-draft Neb-U-Mist jet nebulizer and a Hudson 1730 "T" up-draft Neb-U-Mist II jet nebulizer (Hudson; Temecula, Calif), which were driven by a compressor (Pulmo-Aide; Devilbiss; Somerset, Pa) and by dry compressed air at 6 and 8 L/min. Particle size distribution was measured with a particle sizer (Malvern 2600; Malvern Instruments; Malvern, UK) and drug output for the nebulizer was calculated from the differences in predrug and postdrug volume and concentration. Drug availability was defined as the amount of drug carried in particles less than 5 microns in diameter. Drug availability was greater with the albuterol respiratory solution, due to the surface activity of the preservative benzalkonium chloride, for both nebulizers but particularly for the 1720. Differences in drug availability between nebulizers exceeded fourfold depending on the preparation, the nebulizer, and the nebulizing flow. These differences could not have been predicted from the manufacturer's specifications. The results suggest that prediction of drug availability must be based on measurements with the specific preparation and the specific nebulizer used.

Aerosolized L-693,989 for Pneumocystis carinii prophylaxis in rats.

Water-soluble pneumocandin L-693,989, a potent antipneumocystis agent in the rat model for Pneumocystis carinii pneumonia (PCP), inhibits P. carinii cyst development and effectively prevents the development of PCP when used as a prophylactic agent (D. M. Schmatz, M. A. Powles, D. C. McFadden, L. Pittarelli, J. Balkovec, M. Hammond, R. Zambias, P. Liberator, and J. Anderson, Antimicrob. Agents Chemother. 36:1964-1970, 1992). However, because of limited oral bioavailability, this compound would likely be restricted to parenteral use in humans. As an alternative, the aerosol delivery of L-693,989 was explored to determine the dosing regimen required to prevent the onset of PCP. Rats with latent P. carinii infections were immunosuppressed continuously with dexamethasone to promote the onset of PCP. During the 6-week immunosuppression period, L-693,989 was delivered to rats as a nebulized solution (volume median diameter of 3.8 microns) via a nose exposure inhalation chamber. The efficiency of aerosol delivery to the lungs and the rate of clearance were determined by using radiolabelled compound. It was found that a daily dose of 0.7 micrograms of L-693,989 per lung or a weekly dose of 77.9 micrograms/lung effectively prevented the development of P. carinii cysts and trophozoites as well as the associated pneumonia commonly seen in rats with acute P. carinii infections. These results demonstrate that L-693,989 is potentially useful as an aerosol prophylactic agent for PCP.

Solid-state phase transitions initiated by water vapor sorption of crystalline L-660,711, a leukotriene D4 receptor antagonist.

Significant water vapor sorption at room temperature by the crystalline and lyophilized forms of L-660,711, a potent, selective leukotriene D4 receptor antagonist, has been measured and shown to produce increasingly more nonflowing, semisolid masses with increasing relative humidity. Thermal analysis, SEM, powder X-ray diffraction, solid-state NMR, and thermomicroscopic measurements reveal that water vapor sorbed at room temperature converts the crystalline form to a noncrystalline form resembling the lyophilized sample. Evidence is presented to indicate that L-660,711 has surface active properties with a critical micellization concentration of approximately 1 x 10(-4) M and an ability to form thermotropic and lyotropic mesomorphic phases when the crystal is heated above 80 degrees C in the anhydrous state; it is lyophilized from aqueous solution, and it is exposed to relative humidities at and above 12%, at room temperature.

Effect of compressional force on tablets containing cellulosic disintegrators I: Dimensionless disintegration values.

Spray-dried lactose tablets containing cellulosic disintegrators or microcrystalline cellulose were compressed at different compressional forces. USP disintegration times were measured as a function of pH and compressional force. Two dimensionless quantities were derived from the experimentally determined disintegration times, and their utility in the study of tablet formulations was demonstrated. These dimensionless quantities were used to assess the effect of compressional force and pH on disintegration behavior as well as to compare disintegrator efficiency. Two internally cross-linked sodium carboxymethylcellulose disintegrators were found to be the most efficient; their efficiency increased with increasing compressional force at all pH values.

Phosphorescence studies of the interaction of myelin basic protein with phosphatidylserine vesicles.

Phosphorescence from the lone tryptophan residue has been studied to monitor the interaction of myelin basic protein with phosphatidylserine vesicles. Spectral shifts in the phosphorescence of the protein in a glycerol-buffer (70:30 w/w) solvent at low temperature are consistent with fluorescence data obtained under ambient conditions, indicating that the tryptophan side chain is exposed to the solvent in the free protein but is buried on interaction with a lipid bilayer. Measurements of the phosphorescence intensity and lifetime as a function of temperature reveal a marked protection of the tryptophan to thermally induced quenching in the presence of phosphatidylserine vesicles. Steady-state anisotropy measurements on the tryptophan phosphorescence were used to follow the slow motions of the protein associated with the synthetic bilayer. The observations that the rotational correlation time for the membrane-associated protein is 4 X 10(3) times that anticipated for a molecule the size of basic protein reflects its partial intrinsic character in the membrane.

Phase diagrams for impure lipid systems. Application to lipid/anaesthetic mixtures.

A physical model is presented to describe theoretically the temperature-dependent interactions of lipid bilayers with small molecules such as anaesthetics. Based on an earlier model, a triangular lattice in which each site is occupied by a single lipid chain is constructed and the small (anaesthetic) molecules are assumed to occupy interstitial sites in the centre of each lattice triangle. The phase characteristics of such lipid/anaesthetic mixtures are described in terms of the interaction parameters between lipid-lipid, lipid-anaesthetic and anaesthetic-anaesthetic molecules. Depending on the chemical nature of the interacting species the following three models are formulated: Model I. An interstitial model in which the only perturbation is in the head-group region of the bilayer and direct interactions between neighbouring anaesthetic molecules are taken into account. Model II. Here, only hydrophobic interactions between anaesthetics and lipids are considered. Model III. Both van der Waals' and coulombic interactions are taken into account. Phase diagrams for the three models are obtained by numerical calculation over a wide range of interaction parameters. It is shown that in all three models, lateral phase separation takes place due to the presence of anaesthetics. The heat of transition, however, is found to be virtually independent of the anaesthetic concentration.

Alteration of the erythrocyte ultrastructure and blood viscosity by morphine.

The effects of acute morphine administration on intact erythrocytes and on their flow properties were studied by measuring the mean cell volume, cell geometry, and whole blood and plasma viscosities. Morphine caused a small (2-7%) increase in mean cell volume. Changes in cell geometry were found to be time dependent and most pronounced in concave portions of the red cells. Whole body viscosity was found to decrease upon morphine treatment; this may be due in part to a concurrent decrease in plasma viscosity.