Influence of Dosage Form, Formulation, and Delivery Device on Olfactory Deposition and Clearance: Enhancement of Nose-to-CNS Uptake

Vasa, Dipy M.; O’Donnell, Lauren A.; Wildfong, Peter L.D.

doi:10.1007/s12247-015-9222-9

Cited by 24 publications

(11 citation statements)

References 86 publications

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“…Also, mice may be hurt by the side effect from the inhaled dissolved treatment. Therefore, a lot of optimization, such as infection dose, dosage form, formulation, and delivery device, should be done in the future (Vasa, O'Donnell, & Wildfong, 2015).…”

Section: Discussionmentioning

confidence: 99%

Identification and evaluation of antivirals for Rift Valley fever virus

Lang

Jasperson

et al. 2019

Veterinary Microbiology

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Rift Valley fever virus (RVFV) is an enveloped, negative-sense, ssRNA virus with a tripartite genome that causes morbidity and mortality in both livestock and humans. Although RVFV is mainly circulating in mainland Africa, this arthropod-borne virus is a potential threat to the other parts of the world. No fully licensed vaccines for human or animal use in the U.S., and effective antiviral drugs have not been identified. As virulent RVFV strains are only handled in biosafety level (BSL) 3 or higher level facilities in the U.S., few laboratories have access to RVFV which limits antiviral development. However, it is crucial to develop effective antivirals to protect public and animal health. Animal models that reproduce Rift Valley fever are vital to identifying and developing antiviral compounds. The currently available attenuated RVFV strain, MP12, provides a BSL-2 challenge model virus for preliminary investigations of RVFV prior to using the virulent RVFV strains. All strains of RVFV have a highly conserved genome, indicating that antivirals or vaccines effective against any RVFV strain will most likely be effective for all RVFV strains. Therefore, we hypothesize that the MP12 is a suitable model virus that can be used for identification and evaluation of effective RVF antivirals. The first objective of this project was to establish a mouse model susceptible to MP12 infection. Based on the literature, we selected and screened six different strains of mice to test their susceptibilities to MP12. We found the STAT-1 knockout mice are the most susceptible to MP12 infection based on clinical symptoms, mortality, viremia, virus replication, histopathological, and immunochemical analyses. Importantly, these mice displayed acute-onset hepatitis and delayed-onset encephalitis similar to severe cases of human RVFV infection. Our second objective was to identify potential antiviral drugs in vitro. We developed and employed a cell-based assay using the recombinant MP12 virus expressing Renilla luciferase to screen a library of 727 small compounds purchased from National Institutes of Health. Of the compounds, 23 were identified and further tested for their inhibitory activities on the recombinant MP12 virus expressing green fluorescent protein. Further plaque reduction assays confirmed that two compounds inhibited replication of parental RVFV MP12 strain with limited cytotoxic effects. The 50% inhibitory concentrations using an MP12 multiplicity of infection (MOI) of 2 were 211.4 µM and 139.5 µM, respectively. Our third objective was to evaluate these two candidates, 6-azauridine and mitoxantrone, in vivo using our mouse model. After one-hour post MP12 infection via an intranasal route, treatment was given intranasally twice daily. Mice treated with placebo and 6-azauridine displayed severe weight loss and reached the threshold for euthanasia with obvious neurological signs, while mice treated with ribavirin (a known antiviral drug) or mitoxantrone showed delayed onset of disease. This result indicates that the mitoxantro...

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Section: Discussionmentioning

confidence: 99%

Identification and evaluation of antivirals for Rift Valley fever virus

Lang

Jasperson

et al. 2019

Veterinary Microbiology

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“…Because of numerous disadvantages including a sluggish action and poor bioavailability (40-45%) According to a new World Health Organization (WHO) study, central nervous system (CNS) conditions such as brain cancers, migraine, autism, neurodegenerative disorders (e. g., diseases of Alzheimer's and Parkinson's), and dementia are among the key triggers of human population impairment [6]. Nevertheless, the production of drug therapies for the treatment of brain neurological disorders relies heavily on the capacity of medicinal agents to successfully permeate the blood-brain barrier (BBB) and have a major effect on the brain [7,8]. The brain consists of two major barriers stopping external materials: BBB and BCSF.…”

Section: Introductionmentioning

confidence: 99%

Nose-to-Brain Drug Delivery: An Update to the Alternative Path to Successful Targeted Anti-Migraine Drugs

Chattopadhyay¹,

Das

Sarma

2021

Int J App Pharm

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The Blood-Brain Barrier (BBB) limits transportation to the brain of possible treatment moieties. Specific stimulation of the brain through olfactory and trigeminal neural pathways by BBB has been taken into consideration for the development of a wide spectrum of brain therapeutics. The intranasal delivery path delivers the drugs through the brain, eliminating any side effects and increasing neurotherapeutics performance. Diverse drug delivery systems (DDDss) for reaching the brain via the nasal route have been researched over the past few decades. Large-scale molecular biologics, such as Deoxyribonucleic acid (DNA), gene vectors, and stem cells, can be administered intranasally, as a method for the management of a range of CNS illnesses, including stroke, Parkinson's diseases, multiple sclerosis, Migraine, Alzheimer's diseases, epilepsy, and mental disorders. New DDSs, including nanoparticles, liposomes, and polymeric micelles, have acquired potentials in the nasal mucosa and central nervous system (CNS), as effective means of concentrating the brain without toxicity. Differential nasal cavity structures posed a significant obstacle in ineffective drugs beyond the nasal valve. Pharmaceutical firms have increasingly used emerging techniques for the production of new nasal pharmaceutical drugs to overcome these obstacles. This review aims to identify the new advances in the nasal administration of brain-based DDSs for Migraines.

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“…IN delivery is advantageous over other routes in that therapeutics delivered in this manner will follow a more direct route to the brain [168]. Instead of having to pass the BBB from the circulation, the therapeutic must instead pass through the olfactory and/or trigeminal nerve epithelial layers [130].…”

Section: Delivery Routementioning

confidence: 99%

“…There are, however, challenges with IN delivery. Achieving deposition on the olfactory region for proper administration of the therapeutic is very difficult [72,168].…”

Section: Delivery Routementioning

confidence: 99%

Targeted nano-carriers to combat neurodegeneration

Schlichtmann

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Influence of Dosage Form, Formulation, and Delivery Device on Olfactory Deposition and Clearance: Enhancement of Nose-to-CNS Uptake

Cited by 24 publications

References 86 publications

Identification and evaluation of antivirals for Rift Valley fever virus

Identification and evaluation of antivirals for Rift Valley fever virus

Nose-to-Brain Drug Delivery: An Update to the Alternative Path to Successful Targeted Anti-Migraine Drugs

Targeted nano-carriers to combat neurodegeneration

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