RESUMEN
The pharmacokinetic (PK) profile of a drug after inhalation may differ quite markedly from that seen after dosing by other routes of administration. Drugs may be administered to the lung to elicit a local action or as a portal for systemic delivery of the drug to its site of action elsewhere in the body. Some knowledge of PK is important for both locally- and systemically-acting drugs. For a systemically-acting drug, the plasma concentration-time profile shares some similarities with drug given by the oral or intravenous routes, since the plasma concentrations (after the distribution phase) will be in equilibrium with concentrations at the site of action. For a locally-acting drug, however, the plasma concentrations reflect its fate after it has been absorbed and removed from the airways, and not what is available to its site of action in the lung. Consequently, those typical PK parameters which are determined from plasma concentration measurements, e.g., area under the curve (AUC), Cmax, tmax and post-peak t1/2 may provide information on the deposition and absorption of drugs from the lung; however, the information from these parameters becomes more complicated to decipher for those drugs which are locally-acting in the lung. Additionally, the plasma concentration profile for both locally- and systemically-acting drugs will not only reflect drug absorbed from the lung but also that absorbed from the gastrointestinal (GI) tract from the portion of the dose which is swallowed. This absorption from the GI tract adds a further complication to the interpretation of plasma concentrations, particularly for locally-acting drugs. The influence of physiological and pathological factors needs to be considered in the absorption of some inhaled drugs. The absorption of some hydrophilic drugs is influenced by the inspiratory maneuver used during initial inhalation of the drug, and at later times after deposition. Similarly, the effects of smoking have been shown to increase lung permeability and increase the absorption of certain hydrophilic drugs. The effects of different disease states of the lung have less defined influences on absorption into the systemic circulation.
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Pulmón , Fumar , Administración por Inhalación , Preparaciones Farmacéuticas , Área Bajo la CurvaRESUMEN
Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler. An accompanying open-label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium-99m (99m Tc)-radiolabeled GDC-0214. GDC-0214 plasma concentrations were linear and approximately dose-proportional after both single and multiple doses. Peak plasma concentrations occurred at 15-30 min after dosing. The mean apparent elimination half-life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15-fold less than the plasma protein binding-corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC-0214 was deposited in the lungs and was distributed well to the peripheral airways. 99m Tc-radiolabeled GDC-0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC-0214 exhibited pharmacokinetic properties favorable for inhaled administration.
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Pulmón , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Pulmón/diagnóstico por imagen , CintigrafíaRESUMEN
Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (81mKr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 µg radiolabeled using technetium-99 m [99mTc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; 99mTc aerosol C/P/81mKr gas C/P). Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.
Asunto(s)
Asma , Beclometasona , Administración por Inhalación , Asma/diagnóstico por imagen , Asma/tratamiento farmacológico , Beclometasona/efectos adversos , Combinación de Medicamentos , Fumarato de Formoterol , Glicopirrolato/efectos adversos , Voluntarios Sanos , Humanos , Pulmón/diagnóstico por imagen , Resultado del TratamientoRESUMEN
This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6µg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0µg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.
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Fumarato de Formoterol/administración & dosificación , Fumarato de Formoterol/farmacocinética , Glicopirrolato/administración & dosificación , Glicopirrolato/farmacocinética , Pulmón , Administración por Inhalación , Adulto , Aerosoles/administración & dosificación , Aerosoles/farmacocinética , Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Estudios Cruzados , Combinación de Medicamentos , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacocinética , Cintigrafía , SuspensionesRESUMEN
P-glycoprotein (P-gp) mediated efflux is recognised to alter the absorption and disposition of a diverse range of substrates. Despite evidence showing the presence of P-gp within the lung, relatively little is known about the transporter's effect upon the absorption and distribution of drugs delivered via the pulmonary route. Here, we present data from an intact isolated rat lung model, alongside two isolated mouse lung models using either chemical or genetic inhibition of P-gp. Data from all three models show inhibition of P-gp increases the extent of absorption of a subset of P-gp substrates (e.g. rhodamine 123 and loperamide) whose physico-chemical properties are distinct from those whose pulmonary absorption remained unaffected (e.g. digoxin and saquinavir). This is the first study showing direct evidence of P-gp mediated efflux within an intact lung, a finding that should warrant consideration as part of respiratory drug discovery and development as well as in the understanding of pulmonary pharmacokinetic (PK)-pharmacodynamic (PD) relationships.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Pulmón/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Antiarrítmicos/farmacocinética , Antidiarreicos/farmacocinética , Transporte Biológico , Digoxina/farmacocinética , Perros , Técnicas de Inactivación de Genes , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Loperamida/farmacocinética , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Noqueados , Permeabilidad , Ratas , Ratas Sprague-Dawley , Rodamina 123/farmacocinética , Saquinavir/farmacocinética , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Two-dimensional (2D or planar) imaging with (99m)Tc radiolabels enables quantification of whole-lung and regional lung depositions for orally inhaled drug products. This article recommends standardized methodology for 2D imaging studies. Simultaneous anterior and posterior imaging with a dual-headed gamma camera is preferred, but imaging with a single-headed gamma camera is also acceptable. Correction of raw data for the effects of gamma ray attenuation is considered essential for accurate quantification, for instance, using transmission scanning with a flood-field source of (99m)Tc or (57)Co. Evidence should be provided of the accuracy of the quantification method, for instance, by determining "mass balance." Lung deposition may be expressed as a percentage of ex-valve or ex-device dose, but should also be given as mass of drug when possible. Assessment of regional lung deposition requires delineation of the lung borders, using X-ray computed tomography, radioactive gas scans ((133)Xe or (81m)Kr), or transmission scans. When quantifying regional lung deposition, the lung should be divided into outer (O) and inner (I) zones. A penetration index should be calculated, as the O/I ratio for aerosol, normalized to that for a radioactive gas or transmission scan. A variety of methods can be used to assess lung deposition and distribution. Methodology and results should be documented in detail, so that data from different centers may be compared. The use of appropriate methodology will provide greater confidence in the results of 2D imaging studies, and should allay concerns that such studies are qualitative or semiquantitative in nature.
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Sistemas de Liberación de Medicamentos , Pulmón/diagnóstico por imagen , Cintigrafía/métodos , Radiofármacos/administración & dosificación , Administración por Inhalación , Aerosoles , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Cintigrafía/instrumentación , Cintigrafía/normas , Radiofármacos/química , Radiofármacos/farmacocinética , Tecnecio/química , Distribución TisularRESUMEN
Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man.
Asunto(s)
Sistemas de Liberación de Medicamentos , Pulmón/diagnóstico por imagen , Cintigrafía/métodos , Radiofármacos/administración & dosificación , Administración por Inhalación , Aerosoles , Humanos , Pulmón/metabolismo , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Radiofármacos/química , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.
Asunto(s)
Sistemas de Liberación de Medicamentos , Pulmón/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Administración por Inhalación , Aerosoles , Animales , Diseño de Fármacos , Humanos , Pulmón/diagnóstico por imagen , Nebulizadores y Vaporizadores , Cintigrafía/métodos , Investigación/tendencias , Distribución TisularRESUMEN
BACKGROUND: The I-neb AAD System was designed to deliver aerosol with two different breathing pattern algorithms: the Tidal Breathing Mode (TBM) and the Target Inhalation Mode (TIM). For the purpose of the study, the TBM breathing pattern algorithm was set to guide the subjects to inhalation during tidal breathing with aerosol pulsed during 50-80% of the time spent on inhalation, whereas the TIM breathing pattern was set to guide the subject to a slow and deep inhalation of up to approximately 9 sec with aerosol pulsed for up to 7 sec, leaving 2 sec for particle deposition in the lungs. In TIM, the inspiratory flow was guided to approximately 20 L/min through a built-in resistance in the mouthpiece. METHODS: We have, in a randomized, open-label, crossover study of 12 healthy subjects evaluated lung deposition following administration of a radiolabeled aerosol from the I-neb AAD System with the TBM and TIM breathing patterns. RESULTS: The results showed that mean lung deposition was significantly higher when using the I-neb AAD System with the TIM breathing pattern (73.3%) than with the TBM breathing pattern (62.8%). The mean exhaled fractions were low (<1%) for both breathing patterns. The nebulization time was significantly shorter with the TIM breathing pattern (3.0 min) than with the TBM breathing pattern (4.7 min). CONCLUSIONS: The results of the present study showed that lung deposition with the slow and deep inhalation achieved through the I-neb AAD System in TIM was superior to the lung deposition achieved during tidal breathing in TBM. With the combination of high lung deposition, almost no loss of aerosol during exhalation, and short nebulization time the I-neb AAD System with the TIM breathing pattern should be of special value to patients who require multiple daily dosing of aerosolized medication, are using drugs that should not be wasted into the room air, or would benefit from a more efficient delivery system.
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Sistemas de Liberación de Medicamentos/instrumentación , Pulmón/metabolismo , Nebulizadores y Vaporizadores , Mecánica Respiratoria , Administración por Inhalación , Adulto , Aerosoles , Anciano , Algoritmos , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Pentetato de Tecnecio Tc 99m/administración & dosificación , Pentetato de Tecnecio Tc 99m/farmacocinética , Factores de Tiempo , Adulto JovenRESUMEN
Publication which provides a system-level mapping and assessment of international humanitarian assistance by: defining key criteria for assessing system performance and progress, assessing the systems performance over the past two years against these criteria, presenting new, previously unavailable descriptive statistics, and highlighting some new initiatives in policy and practice. Available in pdf format; 72 pages.
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Agencias Internacionales/organización & administración , Salud Global , Cooperación Internacional , 34009RESUMEN
Aerosolised DNA administration could potentially advance the treatment of inheritable lung diseases, lung malignancies and provide genetic immunisation against infection. Jet nebulisation, the current standard for introducing DNA formulations into the lung, is inherently inefficient. Pressurised metered dose inhalers (pMDIs) offer a potentially more efficacious and convenient alternative, especially for repeat administration. We aim to modify a novel low-energy nanotechnology process to prepare surfactant-coated pDNA nanoparticles for pulmonary gene delivery via a pMDI. Water-in-oil microemulsions containing green fluorescent protein reporter plasmid were snap-frozen and lyophilised. Lyophilised pDNA, in some cases following a surfactant wash, was incorporated into pMDIs with hydrofluoroalkane 134a (HFA134a) propellant and ethanol as cosolvent. To assess biological functionality, A549 human lung epithelial cells were exposed to aerosolised pDNA particles in the presence of dioleoyl-trimethylammonium propane (DOTAP). Transfection studies demonstrated that pDNA biological functionality was maintained following aerosolisation. In vitro toxicity assays (MTT) showed no significant cell viability loss following aerosolised pDNA treatment. We have demonstrated that pDNA particles can be incorporated into an HFA134a formulation and aerosolised using a standard valve and actuator. Particles prepared by this novel process have potential for stable and efficient delivery of pDNA to the lower respiratory tract via standard pMDI technology.
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ADN/administración & dosificación , Inhaladores de Dosis Medida , Tensoactivos/química , Transfección/instrumentación , Administración por Inhalación , Aerosoles/química , Línea Celular , Supervivencia Celular , Células Epiteliales/metabolismo , Diseño de Equipo , Genes Reporteros , Humanos , Pulmón/citología , Plásmidos/administración & dosificación , Transfección/métodosRESUMEN
BACKGROUND: Alginate-based gastroesophageal reflux disease treatments have been used extensively and fall into two main categories. Those containing alginate as the principle active agent and those containing alginate in combination with a significant amount of antacid. METHOD: The effectiveness of the raft formed by a new alginate/antacid suspension (Gaviscon Double Action Liquid, GDAL), in which calcium carbonate was the main antacid ingredient, was compared with those of existing alginate/antacid suspensions. RESULT: GDAL had similar raft strength and improved raft resilience than Gaviscon Liquid (GL), and both were significantly greater than five other products tested. Gastric retention of GDAL was similar to that of GL. CONCLUSION: the in vitro and in vivo performance is maintained in the new GDAL formulation even with higher antacid levels and the product is as good as, or better than, previous formulations.
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Alginatos/administración & dosificación , Antiácidos/administración & dosificación , Química Farmacéutica/instrumentación , Mucosa Gástrica/metabolismo , Estómago/diagnóstico por imagen , Adulto , Alginatos/farmacocinética , Antiácidos/farmacocinética , Química Farmacéutica/métodos , Estudios Cruzados , Combinación de Medicamentos , Interacciones Alimento-Droga/fisiología , Reflujo Gastroesofágico/diagnóstico por imagen , Reflujo Gastroesofágico/tratamiento farmacológico , Ácido Glucurónico/administración & dosificación , Ácido Glucurónico/farmacocinética , Ácidos Hexurónicos/administración & dosificación , Ácidos Hexurónicos/farmacocinética , Humanos , Masculino , Cintigrafía , Estómago/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: The purpose of this study was to investigate the inhalation of a liposomal formulation of amikacin in healthy male volunteers in terms of pulmonary deposition, clearance, and safety following nebulization with a commercial jet nebulizer. METHODS: Amikacin was encapsulated in liposomes comprised of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol via a proprietary manufacturing process (20 mg/mL final amikacin concentration). The liposomes were radiolabeled with (99m)Tc using the tin chloride labeling method. A nominal dose of 120 mg of drug product was loaded into a PARI LC STAR nebulizer, aerosolized using a PARI Boy compressor where subjects inhaled for 20 min. Lung deposition was determined by gamma scintigraphy in three healthy male volunteers at the following time points (0, 1, 3, 6, 12, 24, 48, and 72 h post-administration). RESULTS: Total lung deposition, expressed as a percentage of the emitted dose, was 32.3 +/- 3.4%. The time-dependent retention of radiolabeled liposomes was biphasic with an initial rapid reduction in counts, followed by a slower phase to 48 h. The overall mean retention at 24 and 48 h was 60.4 and 38.3% of the initial dose deposited, respectively. The observed clearance of radiolabel is consistent with clearance of amikacin following aerosol delivery to rats. There were no clinically significant changes in laboratory parameters, vital signs, or ECG. No adverse events including cough or bronchospasm were reported. CONCLUSIONS: Inhalation of a single nominal dose of 120 mg liposomal amikacin results in prolonged retention of drug-loaded liposomes in the lungs of healthy volunteers. The treatment was well tolerated.
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Amicacina/administración & dosificación , Amicacina/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Administración por Inhalación , Aerosoles , Amicacina/efectos adversos , Antibacterianos/efectos adversos , Química Farmacéutica , Volumen Espiratorio Forzado , Humanos , Liposomas , Masculino , Tasa de Depuración Metabólica , Nebulizadores y Vaporizadores , Cintigrafía , Radiofármacos , Valores de Referencia , Reproducibilidad de los Resultados , Pertecnetato de Sodio Tc 99m , Capacidad VitalRESUMEN
OBJECTIVE: We investigated the pulmonary absorption of dihydroergotamine (DHE) mesylate and compared the safety, pharmacokinetic, and metabolic profile of 4 different doses of orally inhaled DHE delivered by the Tempo Inhaler (MAP Pharmaceuticals Inc., Mountain View, CA, USA) with 1.0 mg intravenously (IV) administered DHE in 18 healthy subjects. METHODS: Safety was measured by monitoring adverse events, vital signs, electrocardiograms, spirometry, and changes in biochemical and hematological laboratory values. Liquid chromatography, tandem mass spectrometry was used to determine plasma DHE levels while C(max), t(max), AUC(0-6), AUC(0-48), AUC(0-inf), and t(1/2) of parent DHE and the major bioactive metabolite, 8'OH-DHE. Pharmacokinetic parameters and qualitative spectrograms for DHE and metabolites for all treatment groups were compared after inhaled DHE (MAP0004) and IV DHE 1.0 mg. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. RESULTS: Inhaled DHE resulted in rapid systemic absorption with pharmacokinetic parameters of both parent DHE and 8'OH-DHE similar to those achieved after a 3-minute IV infusion. Post-peak (t(max) approximately 12 minutes) DHE concentrations achieved after 4 actuations ( approximately 0.88 mg respirable dose) of MAP0004 were comparable to those detected after IV administration. The systemic exposure to DHE after 6 actuations of MAP0004 was slightly greater than that achieved after IV administration (geometric mean AUC(0-inf) ratio = 1.24). CONCLUSION: The 4-actuation delivery was well tolerated and provided systemic levels of DHE and 8'OH-DHE slightly lower than IV administration and predicted levels.
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Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/farmacocinética , Dihidroergotamina/efectos adversos , Dihidroergotamina/farmacocinética , Inhaladores de Dosis Medida , Administración por Inhalación , Adulto , Analgésicos no Narcóticos/administración & dosificación , Área Bajo la Curva , Dihidroergotamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , MasculinoRESUMEN
Many new chemical entities are poorly soluble, requiring the use of co-solvents or excipients to produce suitable intravenous formulations for early pre-clinical development studies. There is some evidence in the literature that these formulation components can have significant physiological and physicochemical effects which may alter the distribution and elimination of co-administered drugs. Such effects have the potential to influence the results of pre-clinical pharmacokinetic studies, giving a false impression of a compound's intrinsic pharmacokinetics and frustrating attempts to predict the drug's ultimate clinical pharmacokinetics. This review describes the reported effects of commonly used co-solvents and excipients on drug pharmacokinetics and on physiological systems which are likely to influence drug disposition. Such information will be useful in study design and evaluating data from pharmacokinetic experiments, so that the potential influence of formulation components can be minimised.
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Excipientes/farmacología , Farmacocinética , Ciclodextrinas/farmacología , Evaluación Preclínica de Medicamentos , Emulsiones/farmacología , Humanos , Solubilidad , Solventes/farmacología , Tensoactivos/farmacologíaRESUMEN
PURPOSE: A study was designed to compare differences in insulin aerosol deposition profiles in healthy male and female subjects, as well as examine the effect of mouthpiece cross-sectional shape, volume, and taper on deposition profiles using a developmental AERx pulmonary delivery system. METHODS: Six mouthpieces were screened in the laboratory, and three were selected for clinical investigation: a cylindrical mouthpiece with constant-cross-sectional area, an elliptical mouthpiece with constant-cross-sectional area, and a tapered elliptical mouthpiece with an exit cross-sectional area equal to one half the entrance cross-sectional area. RESULTS: There was no significant difference in the lung dose or in the deposition pattern between males and females (p > 0.05, by ANOVA). The cross-sectional shape of the mouthpiece had no significant effect on the clinical lung dose or the deposition pattern (p > 0.05, by ANOVA), although in vitro testing showed lower emitted dose values with the tapered elliptical mouthpiece (by ANOVA and Duncan's multiple range test, alpha = 0.05). Using the tapered mouthpiece in the clinic resulted in significantly more deposition on the mouthpiece itself when compared to the nontapered mouthpieces. CONCLUSION: Inhalation of insulin using the AERx system was insensitive to differences in male and female respiratory tract geometry across all mouthpiece designs examined.
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Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Nebulizadores y Vaporizadores , Adulto , Aerosoles , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Radiofármacos , Caracteres Sexuales , Pentetato de Tecnecio Tc 99mRESUMEN
Caveolae are morphologically evident as omega-shaped invaginations of the plasma membrane with a diameter of 50-100 nm. They may also exist in a variety of other forms including flattened domains indistinguishable from the plasma membrane itself. At least in some cell types caveolae undertake transport functions including that of the endocytic and transcytotic movement of macromolecules, and indeed microbes and microbial toxins. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit caveolae membrane interactions with the aim to develop of novel cellular or transcellular drug delivery strategies. This overview article will provide: pertinent information on the biology of the caveolae membrane system; review the various caveolae isolation methods; highlight some of the literature evidence showing that caveolae are functional with regard to macromolecule transport; discuss the role that caveolae could fulfill in the pulmonary absorption of therapeutic proteins from alveolar airspace to capillary blood following inhalational drug delivery, and finally review some very recent work showing proof-of-principle that caveolae domains can be targeted in a tissue-specific manner with highly selective ligands.
Asunto(s)
Caveolas/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Vesículas Transportadoras/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Caveolas/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Humanos , Vesículas Transportadoras/efectos de los fármacosRESUMEN
A scintigraphic study was carried out to compare the lung deposition of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in healthy volunteers. Validation of Technetium-99m ((99m)Tc) radiolabeling of the budesonide/lactose blend used in the Clickhaler and excipient-free budesonide used in the Turbuhaler was carried out using a multistage liquid impinger, and compared with reference unlabeled devices. Budesonide was quantified using high-performance liquid chromatography and (99m)Tc by scintillation counting. The percentages (SD) of fine particles (<5.5 microm diameter) from radiolabeled and unlabeled devices were not significantly different (p > 0.05). Mean values for drug and radiolabel, respectively, were 34.6% (2.5) and 31.6% (3.8) for the Clickhaler, and 29.8% (5.5) and 31.4% (5 6) for the Turbuhaler. Fifteen healthy male volunteers received a single dose (2 x 200 microg actuations) from both devices in a double-blinded, double dummy, crossover study. During dosing, each inhalation maneuver was recorded using a computer-linked pressure transducer. To permit accurate determination of radiolabeled drug deposition, the lung margins of each volunteer were determined by Krypton-81m ((81m)Kr) gas imaging. Mean [SD] lung deposition for the Clickhaler (26.8% [6.8], RSD 25.2) was significantly greater (p < 0.001) than for the Turbuhaler (15.8% [6.6], RSD 42.2). Inspiratory flow rate parameters were similar for both devices with peak and mean values of 73 and 51 L/min for the Clickhaler, and 73 and 47 L/min for the Turbuhaler, respectively. These results indicate that, in healthy volunteers, budesonide lung deposition was higher and more consistent with the Clickhaler than with the Turbuhaler.