Dose tolerability of chronically inhaled voriconazole solution in rodents

Tolman, Justin A.; Nelson, Nicole; Bosselmann, Stephanie; Peters, Jay I.; Coalson, Jacqueline J.; Wiederhold, Nathan P.; Williams, Robert O.

doi:10.1016/j.ijpharm.2009.06.003

Cited by 17 publications

(20 citation statements)

References 64 publications

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“…Together with the animal experiments reporting on both the effectiveness [3] and tolerability [7] of inhaled voriconazole, our three cases suggest that the safety and therapeutic potential of inhaled voriconazole therapy are promising and should be investigated in future controlled trials. …”

Section: To the Editorsmentioning

confidence: 69%

“…administration, voriconazole distributes well into tissues, including the lungs [5,6], liver and brain [6]. Studies in rats have shown higher concentrations of voriconazole in wet lung tissue than in plasma after inhalation [4,7], but it is unknown how voriconazole is distributed to other tissues after inhalation. The daily dose used (40 mg t.i.d./40 mg q.d.)…”

Section: To the Editorsmentioning

confidence: 99%

“…HbA1c has only recently been recommended as an appropriate stand-alone diagnostic test for T2DM by the most recent report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [7]. Its diagnostic utility had been questioned prior to this report, principally due to a lack of assay standardisation, leading to inter-centre variability, but recent years have seen the implementation of rigorous standardisation via the National Glycohemoglobin Standardization…”

Section: To the Editorsmentioning

confidence: 99%

See 2 more Smart Citations

Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Hilberg¹,

Andersen²,

Henning³

et al. 2012

Eur Respir J

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Section: To the Editorsmentioning

confidence: 69%

Section: To the Editorsmentioning

confidence: 99%

Section: To the Editorsmentioning

confidence: 99%

See 1 more Smart Citation

Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Hilberg¹,

Andersen²,

Henning³

et al. 2012

Eur Respir J

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“…In this respect, poorly soluble drug particulates may be considered similar to so-called inert particles such as titanium dioxide or carbon black (Lehnert, 1992;Warheit et al, 1997). In addition to the drug classes discussed in this paper, voriconazole and zanamivir have both been reported to induce simple foamy macrophage reactions (Dines et al, 1998;Tolman et al, 2009). A macrophage response is rare with drugs that are more soluble, as they are rapidly absorbed into the blood and dispersed (Owen, 2013).…”

Section: Poorly Soluble Drug Particulate Effectsmentioning

confidence: 99%

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Lewis

Williams

Beck

2013

J of Applied Toxicology

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Successes in the field of respiratory medicines are largely limited to three main target classes: β2 -adrenergic receptor agonists, muscarinic antagonists and corticosteroids. A significant factor in attrition during the development of respiratory medicines is the induction of foamy macrophage responses, particularly, in rats. The term foamy macrophage describes a vacuolated cytoplasmic appearance, seen by light microscopy, which is ultrastructurally characterized by the presence of lysosomal lamellar bodies, neutral lipid droplets or drug particles. We propose a simple classification, based light-heartedly on the theme 'the good, the bad and the ugly', which allows important distinctions to be made between phenotypes, aetiologies and adversity. Foamy macrophages induced in rat lungs by exposure to inhaled β2 -agonists, antimuscarinics and corticosteroids are simple aggregates of uniform cells without other associated pathologies. In contrast, macrophage reactions induced by some other inhaled drug classes are more complex, associated with neutrophilic or lymphocytic infiltrations with/without damage to the adjacent alveolar walls. Foamy macrophage responses induced by inhaled drugs may be ascribed to either phagocytosis of poorly soluble drug particles, or to pharmacology. Both corticosteroids and β2 -agonists increase surfactant synthesis whereas muscarinic antagonists may decrease surfactant breakdown, due to inhibition of phospholipase C, both of which lead to phagocytosis of excess surfactant. Simple foamy macrophage responses are considered non-adverse, whereas ones that are more complex are designated as adverse. The development of foamy macrophage responses has led to confusion in interpretation and we hope this review helps clarify what is in fact a relatively simple, predictable, easily interpretable, commonly induced change.

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“…Although cyclodextrin is not an excipient in an approved FDA inhaled product [20], several reports demonstrated the use cyclodextrin in inhaled formulations. Tolman et al [21,22] previously demonstrated that aerosolized voriconazole nebulized solution that contained a diluted form of the commercially available Vfend®, an IV voriconazole dosage form containing SBECD, is capable of producing clinically relevant lung tissue and plasma concentrations of the drug in animals. However, in this form, voriconazole in lung tissue was not able to be detected 6-8 h after administration of a single inhaled dose in the animal study by Tolman et al [21], while voriconazole dry powder lasted longer in the lungs (up to 24 h) in an animal study by Beinborn et al [23].…”

Section: Introductionmentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Preprint

Self Cite

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Remdesivir, an investigational broad-spectrum antiviral agent, has shown in vitro activity against SARS-CoV-2. To maximize direct delivery to the target site, the lungs, we aim to develop remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces a brittle matrix of nanostructured aggregates that can be sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients (e.g. Captisol®, mannitol, lactose, leucine) exhibited suitable aerosol performance (up to 92.4% FPF and 0.86 µm MMAD). Remdesivir was amorphous after the TFF process, which we hypothesize will provide a benefit for drug dissolution once administered to the lungs. Neither the organic/water processing cosolvent or the rapid freezing rate used during the TFF process affected the chemical stability of remdesivir during processing. In conclusion, TFF is a suitable technology for producing remdesivir dry powder formulations suitable for pulmonary administration.

show abstract

Dose tolerability of chronically inhaled voriconazole solution in rodents

Cited by 17 publications

References 64 publications

Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Remarkably efficient inhaled antifungal monotherapy for invasive pulmonary aspergillosis: Figure 1–

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

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