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.

The choice of jet nebulizer, nebulizing flow, and addition of albuterol affects the output of tobramycin aerosols.

The use of inhaled antibiotics in the treatment of cystic fibrosis has become widespread despite controversy in the literature as to the appropriate dosing regimen and its effectiveness. This study compared two tobramycin (T) preparations (one with and one without the addition of albuterol) using two different jet nebulizers in order to determine if drug output would be affected. Using calibrated flows from a dry compressed gas source of 6 and 8 L/min as well as a specific compressor (Pulmo-Aide), the Hudson 1720 nebulizer was compared with the newer disposable Hudson 1730. The albuterol preparation used in this study was the Ventolin (albuterol) Respirator Solution (VRS). The nebulizers were charged with (1) 2 mL T (80 mg/2 mL) with 0.5 mL VRS (5 mg/mL) and normal saline solution to make the total nebulizer charge of 3 or 4 mL, or (2) 2 mL T and either 1 or 2 mL normal saline solution. A laser diffraction analyzer (Malvern 2600) was used to determine the aerosol particle size distribution. From the distribution, the respirable fraction, which is the fraction of aerosol that could enter and remain in the lungs, was calculated. For all solutions and each particular flow, the Hudson 1730 had a larger respirable fraction of T. The addition of VRS lowered the surface tension of the solution in the nebulizer and resulted in a greater output of T. This effect was most apparent for the 3-mL volume fills of the Hudson 1720. The greatest differences were between the 3-mL nebulizer charges of T using the Hudson 1720 driven by a flow of 6 L/min, which produced 8 mg of T in the respirable fraction, compared with 35 mg produced by the Hudson 1730 driven by a flow of 8 L/min. These results suggest that different nebulizers, different nebulizer solutions, and different techniques of nebulization may result in very different amounts of T aerosol output in the respirable fraction.

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.

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.

PURPOSE: The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. METHODS: This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1-3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. RESULTS: In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng.hr/ml, 385 ng/ml. 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng.hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. CONCLUSIONS: The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.

Diabetes insipidus, acute myelogenous leukemia, and monosomy 7.

Diabetes insipidus together with acute myelogenous leukemia has rarely been seen. Still rarer is the occurrence of monosomy 7 with the two diseases (only six cases reported). A patient who had diabetes insipidus develop before the diagnosis of acute myelogenous leukemia was found at karyotyping to have monosomy 7. Although a specific mechanism whereby monosomy 7 would cause diabetes insipidus has been proposed, some have suggested that monosomy 7 may have its effect by altering cell wall membranes. Others have suggested that acute myelogenous leukemia causes diabetes insipidus by causing infiltrates in the hypothalamus or posterior lobe of the pituitary gland. Magnetic resonance imaging of the patient's brain showed no abnormalities of the hypothalamus or pituitary gland. Lumbar puncture revealed no leukocytes in the cerebrospinal fluid. The authors believe that the cause of diabetes insipidus can be explained in patients with acute myelogenous leukemia by checking for monosomy 7 during karyotyping. Because karyotyping is now more frequently performed in evaluation of patients for chemotherapy or bone marrow transplantation, genetic abnormalities such as monosomy 7 will become increasingly apparent.

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.

Interfacial catalysis and production of a high ratio of leukotriene A4 to 5-HPETE by 5-lipoxygenase in a coupled assay with phospholipase A2.

The activity of purified 5-lipoxygenases (5-LO) shows a requirement for the presence of phosphatidylcholine or other lipids, in addition to Ca2+ and ATP. The enzymatic activity of purified human 5-lipoxygenase was dependent on the ratio of arachidonic acid to phospholipids rather than on the bulk arachidonic acid concentration, suggesting that the concentration of substrate at the lipid-water interface is important for the rate of the 5-LO reaction. Enzyme activity was also examined using vesicles of dimyristoylphosphatidylmethanol/1-palmitoyl-2-arachidonoylphosp hat idylcholine. Using PLA2 to release arachidonic acid from phospholipid, the ratio of leukotriene A4 (detected as trans-LTB4 isomers) to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) accumulated depended on the 5-LO concentration and was relatively independent of the amount of PLA2. The ratio of leukotriene A4 to 5-HPETE production increased with the amount of 5-LO (1-15 micrograms/ml) to reach values (> 10) similar to those observed with ionophore-challenged human leukocytes. The data are consistent with the catalysis of 5-LO occurring at the surface of phospholipid vesicles with the 5-HPETE product being re-utilized by the LTA4 synthase reaction of 5-lipoxygenase under conditions of limiting arachidonic acid availability.

Liposomal drug delivery to the eye and lungs: a preliminary electron microscopy study.

Colloidal gold was used as an electron-dense marker for multilamellar vesicles to study the mechanism of liposome drug delivery to the eye and lung. A gold labelled multilamellar vesicle could be seen in the conjunctiva but there was no evidence of vesicles adsorbed to the epithelial surface of cornea or conjunctiva. In the lung, a free gold particle was isolated in type 1 epithelial cells and many vesicular structures were observed in the alveolar spaces which were not gold labelled. Experiments performed so far indicate that adsorption and not endocytosis was the major mechanism of uptake of drug or marker for multilamellar vesicles except for conjunctiva.

Freeze substitution technique for identifying liposomes incorporated in emulsion and gel preparations.

The freeze-substitution technique was utilized for identifying unilamellar and multilamellar liposomes incorporated in gel or emulsion preparations. Samples of each preparation were rapidly frozen in liquid propane and the ice formed in the process was substituted with acetone containing 2 per cent osmium tetroxide at -70 degrees C. Electron micrographs obtained by both freeze-fracture and freeze-substitution methods showed the presence of either small unilamellar or multilamellar vesicles in all the liposome preparations. Results clearly demonstrated that freeze-substitution is a simple and cost-effective technique in comparison to the traditional freeze-fracture method and can be successfully used to characterize liposomes incorporated in dermatological or cosmetic vehicles.

Liposomal pulmonary drug delivery. I. In vivo disposition of atropine base in solution and liposomal form following endotracheal instillation to the rabbit lung.

The potential of liposomes as carriers for local pulmonary drug delivery was investigated in the rabbit. Atropine base, a model compound for lipophilic drugs, was encapsulated in neutral MLVs and sprayed at the bifurcation of the trachea. Drug concentrations determined in the lung indicated liposomal encapsulation provided higher drug concentrations within pulmonary tissue for a more prolonged period of time as compared to the solution form. Comparison of drug levels in plasma and appearance of drug in urine demonstrated more rapid systemic absorption and elimination of 'free' drug. Greater accessibility of drug in solution to the systemic circulation was reflected in higher atropine concentrations in all internal organs studied. Liposome encapsulation favourably altered the disposition of atropine base when locally administered to the rabbit lung.

A phase II trial of iproplatin (CHIP) in previously treated advanced breast cancer.

Iproplatin (CHIP) was administered to 35 previously treated women with metastatic adenocarcinoma of the breast. The drug was given at a dose of 45 mg/m2 intravenously for 5 consecutive days and was repeated every 28 days. In this trial, there was one partial response and two patients with stable disease out of 29 evaluable patients. The median duration of response in patients with either a partial response or stable disease was 4.8 months. Myelosuppression was the major toxicity, 11 patients had severe thrombocytopenia and 3 severe neutropenia. Mild renal insufficiency, anemia, and nausea and vomiting were also noted. Iproplatin has limited activity in heavily pretreated women with advanced breast carcinoma; further studies in patients less heavily treated may show an improved response rate.

Thrombocytopenia following sustained-release procainamide.

Procainamide hydrochloride-induced thrombocytopenia has infrequently been reported in the past. We report six cases of thrombocytopenia following the administration of the sustained-release form of procainamide. Three of these cases had platelet counts of less than 15,000/microL. The mean time to onset of thrombocytopenia from drug administration was 40 days (range, nine to 71 days). The mean time until normalization of the platelet counts after the drug therapy was stopped was 7.8 +/- 3.1 days (range, four to nine days). Oral prednisone therapy had little apparent benefit. The thrombocytopenia was not part of a systemic lupus erythematosus syndrome. We believe that thrombocytopenia is an important side effect of sustained-release procainamide therapy.

Haemophilus parainfluenzae thoracic empyema.

To our knowledge, thoracic empyema caused by Haemophilus parainfluenzae has not been described previously. A case occurred in the setting of alcoholism and chronic obstructive pulmonary disease. We note the similarity to pulmonary infections with H influenzae and discuss the implications for antibiotic therapy.

Alterations of crossbridge angle induced by beta, gamma-imido-adenosine-triphosphate. Electron microscope and optical diffraction studies on myofibrillar fragments of abdominal muscles of the crayfish Orconectes limosus.

The molecular basis of muscle contraction is thought to consist of cyclic movements of parts of the myosin molecules (crossbridges). Unitl now different states of the proposed crossbridge cycle could be stablilized and demonstrated by electron microscopy only in the case of highly specialized insect flight muscles. In this paper evidence is presented that it is also possible to induce crossbridge positions corresponding to the rigor [16] and the pseudorelaxed state [3] in non-insect muscles. Homogenization of myofibrils of the abdominal flexors of the crayfish Orconectes limosus in rigor or AMP.PNP-containing solutions brings about two different crossbridge patterns: The formation of crossbridges attached to the actin filaments in a mainly acute (rigor) or in a mainly perpendicular angle (pseudo-relaxed). Optical diffraction patterns taken from electron micrographs of sarcomere fragments are likewise compatible with those taken from sarcomeres of insect flight muscles fixed in comparable conditions [2,3].