Site of deposition and absorption of an inhaled hydrophilic solute

AIMS: To characterize the absorption kinetics and bioavailability of an inhaled hydrophilic solute deposited at various sites within the airways. METHODS: Nine healthy nonsmokers received one intravenous, one oropharyngeal and two pulmonary doses of technetium-99 m-labelled diethylene triamine pentaacetic acid ((99m)Tc-DTPA) in an open and crossover fashion. Pulmonary doses were administered as nebulized large and fine droplet-sized aerosols by Pari and UltraVent nebulizers at fairly rapid and slow inhalation flows, respectively. Plasma concentration-time profiles and 24 h urinary excretion of radioactivity were determined. One dose of (99m)Tc-labelled Nanocoll, as a marker of mucociliary clearance (MCC), was also administered by Pari for similar lung deposition as the (99m)Tc-DTPA and followed by repeated chest gamma-imaging. RESULTS: Intrapulmonary deposition patterns of (99m)Tc-DTPA differed significantly (the mean ratio of penetration index (Pari : UltraVent) was 76% with 95% CI 63%, 91%). However, no differences in rate or extent of (99m)Tc-DTPA absorption were detected. Mean absorption time was 1.8 h (mean difference (Pari-UltraVent): -0.1 h with 95% CI -0.6 h, 0.3 h) and the bioavailability was 70% (mean ratio (Pari : UltraVent): 101% with 95% CI 90%, 115%). The pulmonary elimination half-life of (99m)Tc-Nanocoll (8 h and 45 min) was significantly longer than that of (99m)Tc-DTPA (less than 2 h). The oral bioavailability of (99m)Tc-DTPA was estimated to be 3.1%. CONCLUSIONS: The main elimination pathway of the inhaled hydrophilic solute (99m)Tc-DTPA from the lungs is trans-epithelial absorption. Despite different intrapulmonary radioaerosol deposition patterns, as verified by gamma scintigraphy, no differences in (99m)Tc-DTPA absorption kinetics or bioavailability were detected.     

In vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery

Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to evaluate a formulation with a considerably reduced coat weight and gum concentration for colonic drug delivery in vivo using gamma scintigraphy. In vitro studies have found this formulation to be useful for delivery of 5-fluorouracil to the colon. Rapidly disintegrating core tablets containing (99m)Tc-DTPA were prepared and compression coating with 150 mg of granules containing a mixture of xanthan (XG), guar gum (GG) and starch. The ratios of the two gums XG:GG in the coat was kept 10:20. In vitro dissolution studies on XG:GG::10:20 tablets containing (99m)Tc-DTPA were carried out in simulated upper GIT conditions and also in presence of colonic contents. Cumulative percent release of technetium in the upper GIT conditions and transit time amounted to 4%. The total amount of technetium released in the 24 h of the dissolution study was 53+/-3.23%. Upon introduction of cecal content into the dissolution medium (4%), the release of technetium from the compression-coated tablet increased to 78.34+/-5.34%. Gamma scintigraphy studies carried out in six healthy human volunteers showed that the tablet remained intact during its transit through the upper GIT. The anatomical site of disintegration was found to be the ascending colon/hepatic flexure and the disintegration of the tablet started between 4 and 6 h post-dose in all the volunteers with a further spread of tracer into the ascending, transverse, descending and sigmoidal colon.     

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood--brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.5-florouracil and (99m)Tc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8+/-3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.     

Dose variance associated with calibration and administration of radiopharmaceuticals.

Variation in the amounts of radioactivity that is associated with dose calibration and administration of gamma-emitting radioactive drugs was studied. Health systems use radionuclide dose calibrators when they need to assay drugs for radioactivity. However, the radioactive drugs commonly used for therapeutic or diagnostic purposes are compounded and assayed in or administered from containers that differ from those containing the standard reference materials (SRMs). SRMs for four radionuclides--technetium 99m, indium 111, thallium 201, and iodine 131--were drawn up into vials and syringe-needle assemblies of volumes and sizes represented in clinical practice. In each sample, the amount of radioactivity was calculated and compared with values obtained from three dose calibrators. In addition, over a four-month period, 101 samples of technetium Tc 99m medronate injection with a desired activity of 20 mCi were prepared in syringes; the radioactive dose in each syringe was calibrated for administration to a patient at a specific time that day. The amounts of radioactivity at the time of preparation and the time of administration, the amount remaining in the syringe and needle after administration, and the amount reported as administered were recorded. Measurement with the dose calibrators of the SRMs in containers supplied by the National Institute of Standards and Technology showed radioactivity within 10% of the labeled amount, the percentage of variation regulations allow. Measurements of the SRMs in syringe-needle assemblies were within 10% for technetium 99m and thallium 201, 9-16% for iodine 131, and 15-26% for indium 111. The individual doses of technetium 99m medronate injection were, on average, administered on time, but doses were administered up to 75 minutes before and 107 minutes after the calibration time. The mean +/- S.D. amount administered was 19.0 +/- 1.34 mCi. The mean +/- S.D. amount reported administered was 20 +/- 0.24 mCi. How radiopharmaceuticals were dose calibrated and administered influenced the actual dose available to patients.     

Corrections in dose assessment of 99mTc radiolabeled aerosol particles targeted to central human airways using planar gamma camera imaging

The dose of inhaled radiolabeled aerosols is usually assessed using gamma (GC) camera imaging. Because of the complex and inhomogeneous structure of the lung, consisting of soft tissue, the thoracic skeleton, blood vessels, and air spaces, proper attenuation correction coefficients are difficult to evaluate and the estimated doses bear high uncertainty. One hundred milliliters of aerosol boli composed of 100 nm diameter (99m)Tc radiolabeled carbon particles (Technegas) were targeted either to the airways (AW) or to 800-mL volumetric lung depth (alveoli, AL) in 11 healthy volunteers. In addition, 750-mL full breaths (FB) of aerosol were inhaled to a 800-mL lung depth. The deposited dose was measured by collecting aerosol from inhaled and exhaled air stream on filters, which were analyzed for radioactivity. Lung imaging was performed using a planar GC (posterior). Ratios of GC counts to deposited dose (GC/DD) were similar after FB and AL administration, but twofold lower after AW administration (p < 0.01). Associated attenuation correction factors (ACF) were 2.5 +/- 0.5 (FB), 2.2 +/- 0.4 (AL), and 5.5 +/- 1.6 (AW, p < 0.01). Both GC/DD and ACF were highly correlated to the aerosol distribution index (central to peripheral ratio, C/P). After shallow bolus administration there was a negative correlation between body mass index and GC/DD. Inhalation of radioaerosols used in medical diagnosis and therapy in combination with high central airway deposition results in an underestimation of the deposited dose based on planar GC imaging. The aerosol distribution index C/P may provide one suitable indicator for corrections, which should be confirmed in future studies by individual attenuation analysis based on radiotracer transmission measurements.     

Transferrin-conjugated liposomal system for improved delivery of 5-fluorouracil to brain

The objective of this study is to achieve the enhanced delivery of 5-fluorouracil to brain through transferrin-coupled liposomes. 5-Fluorouracil-loaded liposomes were prepared by cast film method and characterized for particle size, shape, percent encapsulation efficiency and in vitro drug release. Biodistribution studies were carried out with the help of radiolabelled 5-fluorouracil. 5-Fluorouracil was labelled with (99m)Tc-DTPA by oxidation-reduction method using stannous chloride and optimized for labelling parameters to get a high labelling efficiency. The in vitro stability was determined to check the efficiency of a system to find out the suitability of the radiolabelled system for in vivo studies. (99m)Tc-DTPA-labelled 5-fluorouracil bearing non-coupled and coupled liposomes were administered intravenously and biodistribution studies were performed. The distribution of 5-fluorouracil via non-coupled and coupled liposomes was determined in various organs, such as lungs, liver, kidneys, spleen and brain, by measuring the radioactivity using a gamma scintillation unit. The results of in vivo studies confirmed a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. An average of 10-fold increase in the brain uptake of the drug was observed after the liposomal delivery of 5-fluorouracil, while the transferrin-coupled liposomes caused a 17-fold increase in the brain uptake of 5-fluorouracil. Therefore, it can be concluded that transferrin-coupled liposomes enhance the brain uptake of the drug, like 5-fluorouracil.     

Nose-to-brain delivery of tacrine

In the treatment of Alzheimer's disease tacrine, a cholinesterase inhibitor, is not the drug of choice due to its low oral bioavailability, extensive hepatic first-pass effect, rapid clearance from the systemic circulation, pronounced hepatotoxicity, and the availability of drugs better than tacrine in the same pharmacological class. Hence, the aim of this investigation was to ascertain the possibility of direct nose-to-brain delivery of tacrine to improve bioavailability, to avoid the first-pass effect and to minimize hepatotoxicity. Tacrine solution (TS) in propylene glycol was radiolabelled with (99m)Tc (technetium) and administered in BALB/c mice intranasally (i.n.) and intravenously (i.v.). Drug concentrations in blood and brain were determined at predetermined time intervals post dosing. Drug targeting efficiency (DTE %) and the brain drug direct transport percentage (DTP %) were calculated to evaluate the brain targeting efficiency. Brain scintigraphy imaging in rabbits was performed to ascertain the uptake of the drug into the brain. Tacrine solution was effectively labelled with (99m)Tc and was found to be stable and suitable for in-vivo studies. Following intranasal administration tacrine was delivered quickly (T(max) 60 min) to the brain compared with intravenous administration (T(max) 120 min). The brain/blood ratios of the drug were found to be higher for [(99m)Tc]TS(i.n.) compared with [(99m)Tc]TS(i.v.) at all time points. The DTE (207.23%) and DTP (51.75%) following intranasal administration suggested that part of tacrine was directly transported to brain from the nasal cavity. Rabbit brain scintigraphy imaging showed higher uptake of the drug into the brain following intranasal administration compared with intravenous administration. The results showed that tacrine could be directly transported into the brain from the nasal cavity and intranasal administration resulted in higher bioavailability of drug with reduced distribution into non-targeted tissues. This selective localization of tacrine in the brain may be helpful in reducing dose, frequency of dosing and dose-dependent side effects, and may prove an interesting new approach in delivery of the drug to the brain for the treatment of Alzheimer's disease.     

Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats

The aim of this work was to study in rats the nasal route for the brain delivery of the vasoactive intestinal peptide (VIP) neuropeptide. After evaluating VIP stability in solutions obtained from nasal washes, the effect of formulation parameters (pH 4-9, 0-1% (w/v) lauroylcarnitine (LC), hypo- or isoosmolality) on the brain uptake of intranasally administered VIP (10(-8)M)/125I-VIP (300,000 cpm/ml) was studied, using an in situ perfusion technique. Brain radioactivity distribution was assessed by quantitative autoradiographic analysis. Results were compared to intravenously administered VIP. With a hypotonic formulation at pH 4 containing 0.1% LC and 1% bovine serum albumin, VIP stability was satisfactory and loss by adsorption was minimal. Using this formulation, around 0.11% of initial radioactivity was found in the brain after 30 min perfusion and was located in the olfactory bulbs, the midbrain and the cerebellum. HPLC analysis of brain and blood extracts demonstrated the presence of intact VIP in brain and its complete degradation in the blood compartment. By intravenous administration, no intact VIP was found either in brain or in blood. In conclusion, intact VIP could be delivered successfully to the brain using the intranasal route for administration.     

Toward modern inhalational bacteriophage therapy: nebulization of bacteriophages of Burkholderia cepacia complex

Antibiotic-resistant bacterial infections have renewed interest in finding substitute methods of treatment. The purpose of the present in vitro study was to investigate the possibility of respiratory delivery of a Burkholderia cepacia complex (BCC) bacteriophage by nebulized aerosol administration. Bacteriophages in isotonic saline were aerosolized with Pari LC star and eFlow nebulizers, at titers with mean value (standard deviation) of 2.15 x 10(8) (1.63 x 10(8)) plaque-forming unit (PFU)/mL in 2.5-mL nebulizer fills. The breathing pattern of an adult was simulated using a pulmonary waveform generator. During breath simulation, the size distributions of the nebulized aerosol were measured using phase doppler anemometry (PDA). Efficiency of nebulizer delivery was subsequently determined by collection of aerosol on low resistance filters and measurement of bacteriophage titers. These filter titers were used as input data to a mathematical lung deposition model to predict regional deposition of bacteriophages in the lung and initial bacteriophage titers in the liquid surface layer of each conducting airway generation. The results suggest that BCC bacteriophages can be nebulized successfully within a reasonable delivery time and predicted titers in the lung indicate that this method may hold potential for treatment of bacterial lung infections common among cystic fibrosis patients.     

Nanostructured lipid carrier (NLC) coated with Chitosan Oligosaccharides and its potential use in ocular drug delivery system

The objective of the present investigation was to explore the potential of the Chitosan Oligosaccharides (COS)-coated NLC (nanostructured lipid carrier) for ocular drug delivery. NLC loaded with flurbiprofen was prepared by melt-ultrasonic method and then coated with COS with a molecular weight of 3000-6000kDa. After coating, the particles reflected spherical morphology with smooth surface under transmission electron microscope (TEM) analysis and a changed zeta potential from -0.446mV to +20.7mV. The ocular bioadhesion property was evaluated by Gamma scintigraphic technique, revealing that the clearance of the formulations labeled with radioactive 99(m)Tc-DTPA was significantly delayed in the presence of COS, and the AUC of the COS-coated formulation had a 7.7-fold increase comparing with non-coated ones. Additionally, enhanced transcorneal penetration was achieved by using the COS coating with a corresponding apparent permeability coefficients (P(app)) which had a 2.4-fold increase comparing with the reference. Consequently, COS coating modified the properties of NLCs and presented a series of notable advantages in ophthalmic application.     

NC100668, a new tracer tested for imaging of venous thromboembolism: pharmacokinetics and metabolism in humans.

The (99m)Tc-complex of NC100668 [Acetyl-Asn-Gln-Glu-Gln-Val-Ser-Pro-Tyr(3-iodo)-Thr-Leu-Leu-Lys-Gly-NC100194] is a new tracer tested for nuclear medical imaging of venous thromboembolism. NC100668 is a 13-amino acid peptide with a Tc-binding chelator [NC100194; -NH-CH2-CH2-N(CH2-CH2-NH-C(CH3)2-C(CH3)=N-OH)2] linked to the C-terminal end. The present study was performed following injection of (99m)Tc-NC100668 in healthy human volunteers with five dose levels of NC100668 (20-2000 microg) and a constant radioactivity dose. The rate at which the radioactivity was cleared from blood was independent of gender and dose of NC100668; more than half of the 82% urinary clearance of radioactivity was obtained 2 h postinjection. The radioactivity in blood was reduced to 50% of initial values within 12 min; this was followed by a more gradual decrease with a half-life of 1.2 h and a terminal elimination half-life of 10.5 h. The plasma concentration of NC100668 decreased rapidly with an initial half-life of 5 to 10 min. The half-life after this initial phase could be estimated for only two of the subjects in the highest-dose group because the NC100668 concentration in the other samples at these time points was below the limit of detection of the liquid chromatography/mass spectrometry (LC/MS) method. LC/MS analyses of urine samples revealed the identity of two metabolites generated from the C-terminal end of the molecule; Gly-NC100194 was identified as the major metabolite and NC100194 as a minor metabolite. The estimated sum of these two metabolites is in the same magnitude as the recoveries of (99m)Tc in these samples, indicating that most of the (99m)Tc excreted in urine is bound to one of these metabolites.     

Accounting for radioactivity before and after nebulization of tobramycin to insure accuracy of quantification of lung deposition.

The ability to predict drug deposition of inhaled drugs used in cystic fibrosis (CF) is important if there is a need to target specific doses of drug to the lungs of individual patients. The gold standard of measuring pulmonary deposition is the quantification of an aerosolized radiolabel either mixed with the drug solution or tagged directly to the compound of interest. Accuracy of the quantification could be assured if there is agreement between the amount of radioactivity before and after administration. Before administration, the radiolabel is concentrated in the well of the nebulizer, whereas after administration, it is distributed throughout the nebulizer, the expiratory filter and connectors, and the upper airway, stomach, trachea, and lung. Not only is the geometry of the distribution that is presented to the gamma camera different, but there are different attenuation factors for the various body tissues. The primary aim of this study was to evaluate the accuracy of the quantification of deposition. Secondary goals were to compare in vitro nebulizer performance with that measured in vivo during the deposition study. Eighty milligrams of tobramycin and technetium bound to human serum albumin was administered to 10 normal adults using a Pari LC Jet Plus (Pari Respiratory Equipment, Inc., Richmond, VA) breath-enhanced nebulizer. Techniques were developed that allowed for the accounting of 99 +/- 2% of the initial radioactivity. The fraction of the rate of lung deposition to total body deposition was the in vivo respirable fraction (0.62 +/- 0.07), which closely agreed with in vitro measurements of respirable fraction (0.62 +/- 0.04). Drug output measured from the change in weight and concentration in the nebulizer systematically overestimated drug output measured by the deposition study. The results indicate that 11.8 of the initial 80 mg would be deposited in the lungs. This technique could be adapted to accurately quantify the amount of deposition on any inhaled therapeutic agent, but caution must be used when extrapolating performance of a nebulizer on the bench to expected deposition in patients.     

Effects of ambient air particulate exposure on blood-gas barrier permeability and lung function

Particulate air pollution is associated with increased risk of pulmonary diseases and detrimental outcomes related to the cardiovascular system, including altered vessel functions. This study's objective was too evaluate the effects of ambient particle exposure on the blood-gas permeability, lung function and Clara cell 16 (CC16) protein release in healthy young subjects. Twenty-nine nonsmokers participated in a randomized, two-factor crossover study with or without biking exercise for 180 min and with 24-h exposure to particle-rich (6169-15,362 particles/cm(3); 7.0-11.6 microg/m(3) PM(2.5); 7.5-15.8 microg/m(3) PM(10-2.5)) or filtered (91-542 particles/cm(3)) air collected above a busy street. The clearance rate of aerosolized (99m)Tc-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) was measured as an index for the alveolar epithelial membrane integrity and permeability of the lung blood-gas barrier after rush-hour exposure. Lung function was assessed using body plethysmography, flow-volume curves, and measurements of the diffusion capacity of carbon monoxide. CC16 was measured in plasma and urine as another marker of alveolar integrity. Particulate matter exposure had no significant effect on the epithelial membrane integrity using the methods available in this study. Exercise increased the clearance rate of (99m)Tc-DTPA indicated by a 6.8% (95% CI: 0.4-12.8%) shorter half-life and this was more pronounced in men than women. Neither particulate matter exposure nor exercise had an effect on the concentration of CC16 in plasma and urine or on the static and dynamic volumes or ventilation distribution of the lungs. The study thus demonstrates increased permeability of the alveolar blood-gas barrier following moderate exercise, whereas exposure to ambient levels of urban air particles has no detectable effects on the alveolar blood-gas barrier or lung function.     

Effect of nebulizer configuration on delivery of aerosolized tobramycin.

Differences in the reported efficacy of aerosolized aminoglycosides may be due, in part, to differences in aerosol delivery. Optimization of delivery systems of bench testing of nebulizers in a manner that simulates clinical conditions can lead to enhanced lung deposition in subsequent clinical studies. In the present study, we assessed the effects of varying nebulizer configuration on the performance of ultrasonic and jet nebulizers. Tobramycin was mixed with a radiotracer (99mTc) to facilitate measurement of nebulizer output and particle size. A piston ventilator provided a simulated breathing pattern, and the dose delivered to a filter corresponded to what would have been inhaled by a patient (percentage of nebulizer charge inhaled). Particle size was measured using a cascade impactor, sampling at 1 L/min. An ultrasonic nebulizer (Ultra-Neb; DeVilbiss, Somerset, PA), ventilated at 20 breaths per minute, charged with 600 mg of tobramycin (in 30-mL volume) and fitted with its standard tubing, was tested with and without the addition of one-way valves to the inspiratory and expiratory ports of the mouthpiece. In order to assess the degree of environmental contamination associated with jet nebulizer therapy, a filter was placed at the expiratory port of all jet nebulizer experiments. The addition of the valves reduced the percentage of charge inhaled from a mean +/- standard deviation (SD) of 29.2% +/- 1.4% to 7.6% +/- 2.3% and reduced mass median aerodynamic diameter [MMAD (sigma g) from 4.3 microns (2.1) to 1.45 microns (1.65)]. A Circulaire (Westmed, Tucson, AZ) jet nebulizer (7 L/min flow, 50 pounds per square inch gauge (psig), 20 breaths per minute, containing 160 mg of tobramycin in a 4-mL volume) was tested in two configurations: using a plain T-piece and using a valved inflatable aerosol chamber. The use of the holding chamber resulted in an almost twofold reduction in MMAD [MMAD (sigma g) = 2.45 microns (2.0); T-piece; 1.25 microns (2.0), holding chamber]. A slight reduction in the percentage of nebulizer charge inhaled using the holding chamber, compared to the plain T-piece, was not statistically significant (mean +/- SD of percentage inhaled with holding chamber = 20.8% +/- 1.6%; with T-piece = 23.6% +/- 0.5%). With both the jet and ultrasonic nebulizers, breathing frequency influenced percentage inhaled, with a higher percentage inhaled at 20 breaths per minute compared to 15 breaths per minute. The use of the plain T-piece at 20 breaths per minute was associated with more environmental contamination than the use of the holding chamber with the same breathing pattern (26.7% +/- 1.0%, T-piece; 4.5% +/- 0.3%, holding chamber, P < 0.0001). We conclude that nebulizer configuration can potentially affect both the amount of aerosol inhaled and the particle size, and needs to be specified precisely in treatment protocols.     

Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption

AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.     

Lung deposition of mannitol powder aerosol in healthy subjects.

Mannitol as a dry powder aerosol is used for bronchoprovocation testing and to enhance mucus clearance in people with excessive airway secretions. The dose and distribution of the deposited aerosol in the lung was investigated using fast single photon emission tomography (SPECT) imaging. Mannitol powder (3 microm particle size) was produced by spray drying and radiolabeled with (99m)Tc-DTPA. Approximately 60 mg of radiolabeled mannitol (containing 52-68 MBq of (99m)Tc-DTPA) was administered to 10 healthy subjects using the Inhalator dry powder inhaler (DPI), and SPECT images (1 min each) were collected. Thirteen percent to 31% of the dose of mannitol loaded in the inhaler deposited in the lungs and the deposited dose correlated positively with the peak inhalation air flow. The regional aerosol lung distribution, as expressed by the penetration index (i.e., ratio of peripheral to central deposition in the lung) varied from 0.31 to 0.88, which however showed no dependency on any flow parameters. The variation in response to the same dose of mannitol within the asthmatic population may in part be explained by these findings.     

Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis.

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.     

The choice of compressor effects the aerosol parameters and the delivery of tobramycin from a single model nebulizer.

Recent U.S. Phase III trials of the aerosolized delivery of tobramycin to cystic fibrosis (CF) patients demonstrated a significant improvement in pulmonary function and in sputum bacterial density. These trials used the Pari LC Plus nebulizer and DeVilbiss Pulmo-Aide compressor. This compressor is not generally available in Europe, and its power requirements do not match the European power supply. Thus alternate compressors were evaluated, using the LC Plus nebulizer, in preparation for European clinical trials. Aerosol particle size distribution, nebulization time (min), and the respirable dose of tobramycin (mg within 1-5 mu) were obtained for seven compressor models. The respirable quantity delivered by each of the European compressors (240 Volts, 50 Hz) was compared to the LC Plus and PulmoAide compressor (120 Volts, at 60 Hz). The U.S. system delivered 71.4 mg of the 300 mg instilled dose within the respirable range; using the European compressors, between 63.0 and 74.8 mg was delivered. With a 97% confidence that the delivered tobramycin was within 20% of the standard, we conclude that the SystAm 23ST, MedicAid CR50 and CR60, Pari Master and the Pari Boy compressors are equivalent to the U.S. standard; the Hercules and the SystAm 26ST compressors were not statistically equivalent to the standard. Using the LC Plus nebulizer, five European compressors delivered doses of TOBI that are similar to the doses delivered by the DeVilbiss PulmoAide compressors, and thus may be expected to produce clinical results similar to those of the U.S. trials.     

Pharmacokinetic parameters of 14C oxithiopurinol in rat.

The study with labelled compound has shown that in rat, as in man, thiopurinol is primarily and rapidly converted into oxithiopurinol. More than 80% of the radioactivity of plasma was identified as oxithiopurinol less than 10 minutes after intravenous or oral administration. The parameters of oxithiopurinol were estimated from the decline of radioactivity in blood from 5 minutes to 8 hours after intravenous administration of 4 microCi/100 g of thiopurinol (8 animals) or oxithiopurinol (5 animals). Half lives of oxithiopurinol t 1/2 (beta) were 2.52 +/- 0.78 hr and 2.90 +/- 1.00 hr and clearance 2.00 +/- 0.36 ml/min. and 3.38 +/- 0.69 respectively. Estimate of renal clearance for oxithiopurinol in rat was 4,17 ml/min. The rapidity of hydroxylation and of elimination of oxithiopurinol might be assumed to be the cause of the apparent ineffectiveness of thiopurinol in vivo on xanthine oxidase activity.     

Pharmacokinetic study of [14C]flutrimazole after oral and intravenous administration in dogs. Comparison with clotrimazole.

This trial involved a comparative study using 6 Beagle dogs on the pharmacokinetics of 14C-labelled 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, CAS 119006-77-8) and [14C]clotrimazole labelled in the imidazole ring. On the basis of a cross-over trial, each animal received a dose of 5 mg/kg (approx. 100 microCi) [14C]flutrimazole and [14C]clotrimazole, both intravenously and orally. The levels in plasma, urine and faeces of the total radioactivity, unchanged drug and the [14C]imidazole formed by metabolization of the unchanged drug were determined. Flutrimazole presented a biological half-life (t1/2) of 14.4 +/- 3.8 h and a clearance (Cl) of 6.7 +/- 0.8 l/h, while the values for clotrimazole were very different: t1/2 4.6 +/- 0.8 h and Cl: 13.6 +/- 1.0 l/h. After oral administration a fraction of absorbed dose (f) of 78 +/- 21% and bioavailability of 8.9 +/- 6.1% were calculated for flutrimazole. For clotrimazole, these were: 52 +/- 10% and 4.9 +/- 1.9%, respectively. Both drugs showed a significant first-pass effect, with 90% of the absorbed dose being metabolized before reaching the systemic circulation. The total recovery of radioactivity in faeces and urine 5 days after i.v. and oral administration was 58% and 68%, respectively, for [14C]flutrimazole, and 81% and 79% for [14C]clotrimazole. In both cases, most of the radioactivity was recovered in the faeces. The high radioactivity obtained in faeces after i.v. administration of both drugs confirms biliary elimination. For both flutrimazole and clotrimazole, less than 1% of the total recovered in the urine after i.v. administration was recovered as unchanged drug.(ABSTRACT TRUNCATED AT 250 WORDS)