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1.
Sci Rep ; 12(1): 4599, 2022 03 29.
Article in English | MEDLINE | ID: covidwho-1931433

ABSTRACT

Dehydration of the upper airways increases risks of respiratory diseases from COVID-19 to asthma and COPD. We find in human volunteer studies involving 464 human subjects in Germany, the US, and India that respiratory droplet generation increases by up to 4 orders of magnitude in dehydration-associated states of advanced age (n = 357), elevated BMI-age (n = 148), strenuous exercise (n = 20) and SARS-CoV-2 infection (n = 87), and falls with hydration of the nose, larynx and trachea by calcium-rich hypertonic salts. We also find in a protocol of exercise-induced airway dehydration that hydration of the airways by calcium-rich salts increases oxygenation relative to a non-treatment control (P < 0.05). In a random control study of COVID-19 positive subjects (n = 40), thrice-a-day delivery of the calcium-rich hypertonic salts (active) suppressed respiratory droplet generation by 51% ± 11% and increased oxygen saturation over three days of treatment by 48.08% ± 9.61% (P < 0.001), while no changes were observed in the nasal-saline control group. Self-reported symptoms significantly declined in the active group and did not decline in the control group. Hydration of the upper airways appears promising as a non-drug approach for reducing risks of respiratory diseases such as COVID-19.


Subject(s)
COVID-19 , Larynx , Exercise , Humans , SARS-CoV-2 , Trachea
2.
Macromol Biosci ; : e2200056, 2022 May 08.
Article in English | MEDLINE | ID: covidwho-1826074

ABSTRACT

The rise of the novel virus SARS-CoV2 which causes the disease known as COVID-19 has led to a global pandemic claiming millions of lives. With no clinically approved treatment for COVID-19, physicians initially struggled to treat the disease, and a need remains for improved antiviral therapies in this area. It is conceived early in the pandemic that an inhalable formulation of the drug remdesivir which directly targets the virus at the site of infection could improve therapeutic outcomes in COVID-19. A set of requirements are developed that would be conducive to rapid drug approval: 1) try to use GRAS reagents 2) minimize excipient concentration and 3) achieve a working concentration of 5 mg/mL remdesivir to obtain a deliverable dose which is 5-10% of the IV dose. In this work, it is discovered that Poly(2-oxazoline) block copolymers can stabilize drug nanocrystal suspensions and provide suitable formulation characteristics for aerosol delivery while maintaining antiviral efficacy. The authors believe POx block copolymers can be used as a semi-ubiquitous stabilizer for the rapid development of nanocrystal formulations for new and existing diseases.

3.
CPT Pharmacometrics Syst Pharmacol ; 10(2): 89-99, 2021 02.
Article in English | MEDLINE | ID: covidwho-966959

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak initiated the global coronavirus disease 2019 (COVID-19) pandemic resulting in 42.9 million confirmed infections and > 1.1 million deaths worldwide as of October 26, 2020. Remdesivir is a broad-spectrum nucleotide prodrug shown to be effective against enzootic coronaviruses. The pharmacokinetics (PKs) of remdesivir in plasma have recently been described. However, the distribution of its active metabolite nucleoside triphosphate (NTP) to the site of pulmonary infection is unknown in humans. Our objective was to use existing in vivo mouse PK data for remdesivir and its metabolites to develop a mechanism-based model to allometrically scale and simulate the human PK of remdesivir in plasma and NTP in lung homogenate. Remdesivir and GS-441524 concentrations in plasma and total phosphorylated nucleoside concentrations in lung homogenate from Ces1c-/- mice administered 25 or 50 mg/kg of remdesivir subcutaneously were simultaneously fit to estimate PK parameters. The mouse PK model was allometrically scaled to predict human PK parameters to simulate the clinically recommended 200 mg loading dose followed by 100 mg daily maintenance doses administered as 30-minute intravenous infusions. Simulations of unbound remdesivir concentrations in human plasma were below 2.48 µM, the 90% maximal inhibitory concentration for SARS-CoV-2 inhibition in vitro. Simulations of NTP in the lungs were below high efficacy in vitro thresholds. We have identified a need for alternative dosing strategies to achieve more efficacious concentrations of NTP in human lungs, perhaps by reformulating remdesivir for direct pulmonary delivery.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Models, Animal , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Alanine/pharmacokinetics , Alanine/therapeutic use , Animals , Antiviral Agents/therapeutic use , COVID-19/metabolism , Cells, Cultured , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Species Specificity
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