Inhalation Route Of Administration Research Articles

Acute and Subacute Toxicity Assessment of Andrographolide-2-hydroxypropyl-β-cyclodextrin Complex via Oral and Inhalation Route of Administration in Sprague-Dawley Rats.

Objective Acute and subacute toxicity analysis of AND-2-HyP-β-CYD complex was conducted in Sprague-Dawley (SD) rats following oral and inhalation routes of administration. Methods and Results Single dose acute toxicity was carried out at 2000 mg/kg of AND-2-HyP-β-CYD complex, while the doses of 200, 400, and 666 mg/kg were administered, over a period of 28 days under repeated dose oral toxicity study. Hence, LD50 (lethal dose) was found to be >2000 mg/kg in addition to NOAEL (no observed adverse effect level) of 666 mg/kg. Correspondingly, single dose acute inhalation toxicity of AND-2-HyP-β-CYD complex was carried out at 5 mg/L/4 h/day and subacute inhalation toxicity at 0.5, 1, and 1.66 mg/L/4 h/day over a period of 28 days. The NOAEL and LOAEL (lowest observed adverse effect level) were estimated to be 0.5 mg/L/4 h/day and 1 mg/L/4 h/day, respectively. Conclusion The findings of the present study would further be useful in assessing and utilizing the medicinal and therapeutic benefits of AND-2-HyP-β-CYD complex.

Physiologically Based Pharmacokinetic Modelling of Inhaled Nemiralisib: Mechanistic Components for Pulmonary Absorption, Systemic Distribution, and Oral Absorption.

Background and ObjectivesPhysiologically based pharmacokinetic (PBPK) modelling has evolved to accommodate different routes of drug administration and enables prediction of drug concentrations in tissues as well as plasma. The inhalation route of administration has proven successful in treating respiratory diseases but can also be used for rapid systemic delivery, holding great promise for treatment of diseases requiring systemic exposure. The objective of this work was to develop a PBPK model that predicts plasma and tissue concentrations following inhalation administration of the PI3Kδ inhibitor nemiralisib.MethodsA PBPK model was built in GastroPlus® that includes a complete mechanistic description of pulmonary absorption, systemic distribution and oral absorption following inhalation administration of nemiralisib. The availability of clinical data obtained after intravenous, oral and inhalation administration enabled validation of the model with observed data and accurate assessment of pulmonary drug absorption. The PBPK model described in this study incorporates novel use of key parameters such as lung systemic absorption rate constants derived from human physiological lung blood flows, and implementation of the specific permeability-surface area product per millilitre of tissue cell volume (SpecPStc) to predict tissue distribution.ResultsThe inhaled PBPK model was verified using plasma and bronchoalveolar lavage fluid concentration data obtained in human subjects. Prediction of tissue concentrations using the permeability-limited systemic disposition tissue model was further validated using tissue concentration data obtained in the rat following intravenous infusion administration to steady state.ConclusionsFully mechanistic inhaled PBPK models such as the model described herein could be applied for cross molecule assessments with respect to lung retention and systemic exposure, both in terms of pharmacology and toxicology, and may facilitate clinical indication selection.

Protamine sulphate coated poly (lactide-co-glycolide) nanoparticles of MUC-1 peptide improved cellular uptake and cytokine release in mouse antigen presenting cells

Aim MUC-1-peptide (M-1-pep) loaded poly (lactide-co-glycolide) nanoparticles were coated with protamine sulphate (PS), M-1-pep-PS-P-NPs for targeting antigen presenting cells (APCs) to evoke cytokine release. Methods and results M-1-pep-PS-P-NPs were tailored by emulsion-diffusion evaporation method and characterised in vitro under a set of rigorous parameters. The average particle size and zeta potential of optimised M-1-pep-PS-P-B-NPs was measured to be 132.21 ± 30.71 nm and 6.29 ± 0.71 mV, significantly (p < 0.01) higher than 71.24 ± 17.76-nm and −43.41 ± 3.37 mV of M-1-pep-P-NPs. Further, 50-μg/ml concentration of M-1-pep-PS-P-B-NPs displayed 82.4% cellular uptake in RAW 264.7 cells calculated in setting of fluorescence intensity significantly (p < 0.05) elevated than 63.1% of M-1-pep-P-NPs. Consistent to quantitative results, M-1-pep-PS-P-B-NPs also confirmed advanced cellular uptake (CU) in RAW 264.7 cells in contrast to M-1-pep-P-NPs suppose to be through multiple mechanisms including phagocytosis and clathrin mediated endocytosis. Conclusion M-1-pep-PS-P-B-NPs must be evaluated in vivo through inhalation route of administration for antitumor prospective in lung cancer xenograft model.

Gender Influences Self-Reported Use Patterns and Demographics in Canadian Cannabis Users

Abstract Objectives With federal legalization of cannabis in Canada and hemp in the USA, there is much interest in consumer demographics and use patterns. The objective of this study was to examine gender differences in cannabis use patterns and demographics in Southwestern Ontario, Canada. Methods A 31 question, online market research survey was conducted on past and present cannabis use from March 2018 to October 2019, including Canadian respondents before and after federal cannabis legalization. The associations between gender and self-reported use reason and frequency, route of administration, cannabinoid, and life stage when starting were assessed. Possible differences were assessed by the Chi Square test and two sample t-test (age only). Results There were 2264 male and 1830 female respondents to the survey, with an average age of 34 ± 13 years. Across genders, the majority of users first started in high school (59.5%). Gender was associated with frequency of use (P &amp;lt; 0.001), higher proportions of males (73.9%) than females (61.1%) were daily users. Males more often reported using inhalation routes of administration, both vapour (43.6% M vs. 30.7% F) and smoking (85.3% M vs. 77.9% F) (P &amp;lt; 0.001). Interestingly, there were no significant differences in the use of sublingual (13.5% total), oral (47.0%) or suppository (0.6%) products between the groups. A greater proportion of males reported recreational cannabis use (79.6% M vs. 72.7% F) (P &amp;lt; 0.001). This agrees with an association between gender and reason for use for which a greater proportion of males reported using cannabis to socialize/relax (68.5% M vs. 54.8% F) and to receive a high (33.0% M vs. 22.6% F) (P &amp;lt; 0.001). Furthermore, the psychoactive component of cannabis, THC, was the most frequently consumed cannabinoid among a greater proportion of males (38.3%) than females (25.7%). Interestingly, there were equal proportions of males and females using cannabis for digestion, controlling pain, and reducing seizures. Conclusions There are significant associations between gender and cannabis use in central Canada. Males and females report using cannabis for different reasons and in different ways and frequencies. With further research there is great potential for cannabis in health and wellness and these data are essential components to inform study design and progress this research area forward. Funding Sources KGK Science Inc.

Non-small cell lung cancer tumour antigen, MUC-1 peptide-loaded non-aggregated poly (lactide-co-glycolide) nanoparticles augmented cellular uptake in mouse professional antigen-presenting cells: optimisation and characterisation

Aim: MUC-1 lipopeptide vaccine exhibited immense potential in the treatment of non-small cell lung cancer (NSCLC) in both preclinical and clinical trials. However, it lacks triggering of mucosal immunity at the site of action. Therefore, in present investigation, MUC-1 peptide-loaded poly(lactide-co-glycolide) nanoparticles (MUC-1 peptide-PLGA-NPs) and MUC-1 peptide-loaded poly(lactide-co-glycolide) non-aggregated nanoparticles (MUC-1 peptide-PLGA-NA-NPs) using Central Composite Design (CCD) were customised.Methods and Results: The mean particle size of MUC-1 peptide PLGA-NPs was estimated to be 176.7 ± 32.7 nm, significantly (p < 0.05) higher than 100.3 ± 24.3 nm of MUC-1 peptide-PLGA-NA-NPs. Furthermore, integrity and stability of MUC-1 were maintained in MUC-1 peptide PLGA-NA-NPs. MUC-1 peptide-PLGA-NA-NPs exhibited augmented cellular uptake in mouse RAW264.7 macrophages preferably by clathrin-mediated endocytosis pathway as compared to phagocytosis followed by MUC-1-peptide PLGA-NPs owing to size ≤100 nm, and spherical shape.Conclusion: MUC-1 peptide-PLGA-NA-NPs may be a potential candidate to study antitumor potential in xenograft model of NSCLC through inhalation route of administration.

Aerosol Delivery of siRNA to the Lungs. Part 2: Nanocarrier-based Delivery Systems.

In this article, applications of engineered nanoparticles containing siRNA for inhalation delivery are reviewed and discussed. Diseases with identified protein malfunctions may be mitigated through the use of well-designed siRNA therapeutics. The inhalation route of administration provides local delivery of siRNA therapeutics to the lungs for various pulmonary diseases. A siRNA delivery system can be used to overcome the barriers of pulmonary delivery, such as anatomical barriers, mucociliary clearance, cough clearance, and alveolar macrophage clearance. Apart from naked siRNA aerosol delivery, previously studied siRNA carrier systems include those of lipidic, polymeric, peptide, or inorganic origin. These delivery systems can achieve pulmonary delivery through the generation of an aerosol via an inhaler or nebulizer. The preparation methodologies for these siRNA nanocarrier systems will be discussed herein. The use of inhalable nanocarrier siRNA delivery systems have barriers to their effective delivery, but overcoming these constraints while formulating a safe and effective delivery system will offer unique advances to the field of inhaled medicine.

Aerosol Delivery of siRNA to the Lungs. Part 1: Rationale for Gene Delivery Systems.

This article reviews the pulmonary route of administration, aerosol delivery devices, characterization of pulmonary drug delivery systems, and discusses the rationale for inhaled delivery of siRNA. Diseases with known protein malfunctions may be mitigated through the use of siRNA therapeutics. The inhalation route of administration provides local delivery of siRNA therapeutics for the treatment of various pulmonary diseases, however barriers to pulmonary delivery and intracellular delivery of siRNA exists. siRNA loaded nanocarriers can be used to overcome the barriers associated with the pulmonary route, such as anatomical barriers, mucociliary clearance, and alveolar macrophage clearance. Apart from naked siRNA aerosol delivery, previously studied siRNA carrier systems comprise of lipidic, polymeric, peptide, or inorganic origin. Such siRNA delivery systems formulated as aerosols can be successfully delivered via an inhaler or nebulizer to the pulmonary region. Preclinical animal investigations of inhaled siRNA therapeutics rely on intratracheal and intranasal siRNA and siRNA nanocarrier delivery. Aerosolized siRNA delivery systems may be characterized using in vitro techniques, such as dissolution test, inertial cascade impaction, delivered dose uniformity assay, laser diffraction, and laser Doppler velocimetry. The ex vivo techniques used to characterize pulmonary administered formulations include the isolated perfused lung model. In vivo techniques like gamma scintigraphy, 3D SPECT, PET, MRI, fluorescence imaging and pharmacokinetic/pharmacodynamics analysis may be used for evaluation of aerosolized siRNA delivery systems. The use of inhalable siRNA delivery systems encounters barriers to their delivery, however overcoming the barriers while formulating a safe and effective delivery system will offer unique advances to the field of inhaled medicine.

Inhalable nanostructured lipid particles of 9-bromo-noscapine, a tubulin-binding cytotoxic agent: Invitro and in vivo studies

9-Bromo-noscapine (9-Br-Nos) alters tubulin polymerization in non-small cell lung cancer cells differently from noscapine. However, clinical applications of 9-Br-Nos are limited owing to poor aqueous solubility and high lipophilicity that eventually lead to suboptimal therapeutic efficacy at the site of action. Hence, 9-Br-Nos loaded nanostructured lipid particles (9-Br-Nos-NLPs) were prepared by nanoemulsion method to reduce the particle size below 100nm. To impart the inhalable and rapid release (RR) attributes, 9-Br-Nos-NLPs were treated with spray dried lactose and effervescent excipients to generate, 9-Br-Nos-RR-NLPs. The mean particle and aerodynamic size of 9-Br-Nos-NLPs were measured to be 13.4±3.2nm and 2.3±1.5μm, significantly (P<0.05) lower than 19.4±6.1nm and 3.1±1.8μm of 9-Br-Nos-RR-NLPs. In addition, zeta-potential of 9-Br-Nos-NLPs was examined to be −9.54±0.16mV, significantly (P<0.05) lower than −7.23±0.10mV of 9-Br-Nos-RR-NLPs. Hence, both formulations were found to be optimum for pulmonary delivery through inhalation route of administration. Next, 9-Br-Nos-RR-NLPs exhibited enhanced cytotoxicity, apoptosis and cellular uptake in A549, lung cancer cells, as compared to 9-Br-Nos-NLPs and 9-Br-Nos suspension. This may be attributed to enhanced drug delivery and internalization character of 9-Br-Nos-RR-NLPs by energy-dependent endocytosis and passive diffusion mechanism. Pharmacokinetic and distribution analysis demonstrated the superiority of 9-Br-Nos-RR-NLPs that exhibited ∼1.12 and ∼1.75-folds enhancement in half-life of the drug as compared to 9-Br-Nos-NLPs and 9-Br-Nos powder following inhalation route. Continuation to this, 9-Br-Nos-RR-NLPs also displayed ∼3.75-fold increment in half-life of the drug in lungs, as compared to 9-Br-Nos suspension following intravenous route of administration. Furthermore, enhanced drug exposure was measured in terms of AUClast in lungs following administration of 9-Br-Nos-RR-NLPs, as compared to 9-Br-Nos-NLPs, 9-Br-Nos powder and 9-Br-Nos suspension. This may be attributed to rapid dispersion, enhanced dissolution and deep lung deposition of nanoparticles following inhalation route. Therefore, inhalable 9-Br-Nos-RR-NLPs claims further in depth in vivo tumor regression study to scale up the technology for clinical applications.

Educational and supportive interventions for improving adherence to inhalation therapy in people with chronic respiratory diseases: A systematic review protocol

Review question/objective The objective of this systematic review is to identify the best available research evidence related to the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy in people with chronic respiratory diseases, focusing on measures of adherence and health outcomes. The specific review questions to be addressed are: 1. What is the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy in terms of inhalation regimens and inhalation techniques in people with chronic respiratory diseases? 2. What is the effectiveness of educational and supportive interventions for improving adherence to inhalation therapy on health service utilization and patient outcomes including symptoms, pulmonary function, and quality of life? 3. What is the effectiveness of various designs, in terms of components, modes and intensities, of educational and supportive interventions for improving adherence to inhalation therapy? Inclusion criteria Types of participants This review will consider studies that include adults aged 18 or above, with a clinical diagnosis of chronic respiratory disease and prescribed self-administered inhalation therapy as a long term regular treatment, irrespective of the type of inhaler used. For the purposes of this review, "chronic respiratory diseases" is defined by WHO in 2007 as "the chronic diseases of the airways and other structures of the lung" (p.5). 1 Inhalation therapy is defined as "a treatment in which a substance is administered to the respiratory tract with inspired air". 6 This review will focus on inhalation of drugs. Those studies with prescribed administration of oxygen and water will be excluded. There is no universal standard for how long a treatment is undertaken to be defined as a "long term treatment". Acute episodic drug treatments, such as a course of antibiotics, will be excluded. Types of interventions of interest All educational interventions, with or without supportive programs, designed to improve the chronic respiratory disease sufferers inhalation technique and adherence to their prescribed inhalation therapy will be considered. Those studies that involve comparison of different types of inhalation medications, inhaler devices or inhalation methods to improve the adherence to inhalation therapy will be excluded. For the TRUNCATED AT 350 WORDS

Metabolism and Disposition of Vilanterol, a Long-Actingβ2-Adrenoceptor Agonist for Inhalation Use in Humans

The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration.

Discovery of Diaryl Imidazolidin-2-one Derivatives, a Novel Class of Muscarinic M3 Selective Antagonists (Part 1)

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.

Δ9-Tetrahydrocannbinol Accounts for the Antinociceptive, Hypothermic, and Cataleptic Effects of Marijuana in Mice

Although it is widely accepted that delta9-tetrahydrocannabinol (delta9-THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that delta9-THC mediates these effects through a CB1 receptor mechanism of action. First, the effects of delta9-THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated delta9-THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal delta9-THC but similar levels of other cannabinoids) that were impregnated with varying quantities of delta9-THC. To assess doses, delta9-THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and delta9-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB1 antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]. Importantly, the blood and brain levels of delta9-THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-delta9-THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from delta9-THC content acting at CB1 receptors and that the non-delta9-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.

Pulmonary delivery of TH9507, a growth hormone releasing factor analogue, in the dog

A modified growth hormone releasing factor (GRF; TH9507), a 44 amino acid peptide analogue of natural human growth hormone releasing factor, is being developed for the treatment of age-associated conditions resulting from diminished growth hormone (GH) secretion. The inhalation route of administration is being considered as an alternative to subcutaneous injection. A study was undertaken in dogs to investigate the absorption of TH9507 following pulmonary delivery. Male beagle dogs were administered TH9507 by intratracheal dry powder insufflation and subcutaneous injection at doses of approximately 375 and 38 μg/kg, respectively. In a separate study, male and female dogs received 100 μg/kg intravenously. Blood samples were collected at selected sampling times after dosing and plasma levels of TH9507 were measured by radioimmunoassay. The bioavailability by the inhaled route was 41% relative to subcutaneous dosing, with an absolute bioavailability estimated at 13%. No significant difference was observed for the terminal half-life of TH9507 after intratracheal (39 min) and subcutaneous (26 min) administrations. The mean residence time (MRT) was greater following intratracheal administration (74 min versus 52 min; P<0.01). These data indicate that the delivery of the TH9507 by the inhalation route may provide a suitable alternative to subcutaneous injection.

Dermal and inhalation acute toxic class methods: test procedures and biometric evaluations for the Globally Harmonized Classification System.

The acute toxic class (ATC) methods were developed for determining LD(50)/LC(50) estimates of chemical substances with significantly fewer animals than needed when applying conventional LD(50)/LC(50) tests. The ATC methods are sequential stepwise procedures with fixed starting doses/concentrations and a maximum of six animals used per dose/concentration. The numbers of dead/moribund animals determine whether further testing is necessary or whether the test is terminated. In recent years we have developed classification procedures for the oral, dermal and inhalation routes of administration by using biometric methods. The biometric approach assumes a probit model for the mortality probability of a single animal and assigns the chemical to that toxicity class for which the best concordance is achieved between the statistically expected and the observed numbers of dead/moribund animals at the various steps of the test procedure. In previous publications we have demonstrated the validity of the biometric ATC methods on the basis of data obtained for the oral ATC method in two-animal ring studies with 15 participants from six countries. Although the test procedures and biometric evaluations for the dermal and inhalation ATC methods have already been published, there was a need for an adaptation of the classification schemes to the starting doses/concentrations of the Globally Harmonized Classification System (GHS) recently adopted by the Organization for Economic Co-operation and Development (OECD). Here we present the biometric evaluation of the dermal and inhalation ATC methods for the starting doses/concentrations of the GHS and of some other international classification systems still in use. We have developed new test procedures and decision rules for the dermal and inhalation ATC methods, which require significantly fewer animals to provide predictions of toxicity classes, that are equally good or even better than those achieved by using the conventional LD(50)/LC(50) methods. In order to cope with rather narrow dose/concentration classes of the GHS we have, as in our previous publications, combined the outcome of all results that can be obtained during testing for the allocation to one of the defined toxicity classes of the GHS. Our results strongly recommend the deletion of the dermal LD(50) and the inhalation LC(50) test as regulatory tests and the adoption of the dermal and inhalation ATC methods as internationally accepted alternatives.

Pharmacological effects of methamphetamine and other stimulants via inhalation exposure

The effects of methamphetamine–HCl, methcathinone–HCl, cocaine and ephedrine on locomotor stimulation were compared between inhalation exposure and i.v. injection in mice. Methamphetamine–HCl was readily volatilized upon heating at 300°C in a glass pipe with only trace amounts of amphetamine being produced. The ED50 dose (9.4 and 6.5 μmol/kg for inhalation exposure and i.v. injections, respectively) and biodisposition of methamphetamine–HCl were similar for both routes of administration. Methcathinone–HCl and cocaine were readily volatilized. Their dose response profiles also appeared similar for both routes of administration. Ephedrine did not appear to be easily volatilized and was only effective in stimulating locomotor activity after i.v. administration. These findings indicate that inhalation exposure to methamphetamine–HCl, cocaine and methcathinone possess similar pharmacological characteristics as the i.v. route of administration. In particular, this model may have implications in predicting the pharmacological activity of various stimulants via the inhalation route of administration.

An overview of the toxicology of HFA-134a (1,1,1,2-tetrafluoroethane)

1. This paper reviews the results of preclinical toxicology studies on HFA-134a carried out by Glaxo Research and Development Ltd. 2. A comprehensive range of studies was conducted in animal models suitable for the type of investigation. 3. The inhalation route of administration was used in all in vivo studies (with the exception of local tolerance and sensitisation studies) as patients will be exposed only to vapour during actuation of metered-dose inhalers. Cell cultures used for in vitro studies were also exposed to the vapour. 4. There was no mortality of rodents or dogs at extremely high vapour concentrations (81%v/v) 5. HFA-134a was considered not to be toxic or oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.