SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial

Tandon, Monika; Wang, Wen; Moore, Keith M.; Winchester, Stephen; Tu, Yuan-Po; Miller, Chris; Kodgule, Rahul; Pendse, Amol; Rangwala, Shabbir; Joshi, Shashank

doi:10.1016/j.lansea.2022.100036

Cited by 26 publications

(17 citation statements)

References 18 publications

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“…The NO donor needs to undergo minimal degradation in the infusion pump for 1 week or more. Third, NO-releasing nasal sprays have proven to be highly effective in mitigating viral infections including COVID-19 . The GSNO solution stabilized by CDs may be a formulation that is amenable for storage and releases NO for a prolonged period of time in the respiratory tract.…”

Section: Resultsmentioning

confidence: 99%

“…Third, NO-releasing nasal sprays have proven to be highly effective in mitigating viral infections including COVID-19. 66 The GSNO solution stabilized by CDs may be a formulation that is amenable for storage and releases NO for a prolonged period of time in the respiratory tract. GSNO-CD solutions with sustained NO delivery may also promote other therapeutic applications for diseases, such as cancer, stroke, asthma, embolization, and cystic fibrosis.…”

Section: No Release and Antibacterial Properties Of Catheters Filled ...mentioning

confidence: 99%

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Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Wang

Lao

et al. 2022

ACS Biomater. Sci. Eng.

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S-Nitrosoglutathione (GSNO) is a nontoxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host−guest chemistry-based strategy to modulate the GSNO reactivity and NO release kinetics for the design of antiinfective catheters and hydrogels. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host−guest complexation reduces the decomposition reactivity of GSNO in the order of αCD > γCD > hydroxypropyl βCD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37 °C, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in αCD undergoes a conformational change that significantly reduces the S−NO bond distance and increases its stability. The calculated S−NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-αCD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains, including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

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Section: Resultsmentioning

confidence: 99%

Section: No Release and Antibacterial Properties Of Catheters Filled ...mentioning

confidence: 99%

Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Wang

Lao

et al. 2022

ACS Biomater. Sci. Eng.

View full text Add to dashboard Cite

show abstract

“…The NO donor needs to undergo minimal degradation in the infusion pump for one week or more. Third, NO-releasing nasal sprays have proven to be highly effective in mitigating viral infections including COVID-19 [60]. The GSNO solution stabilized by CDs may be a formulation that is amenable for storage and releases NO for a prolonged period of time in the respiratory tract.…”

Section: No Release and Antibacterial Properties Of Catheters Filled ...mentioning

confidence: 99%

Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection

Wang

Lao

et al. 2022

Preprint

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S-nitrosoglutathione (GSNO) is a non-toxic nitric oxide (NO)-donating compound that occurs naturally in the human body. The use of GSNO to deliver exogenous NO for therapeutic and protective applications is limited by the high lability of dissolved GSNO in aqueous formulations. In this paper, we report a host-guest chemistry-based strategy to modulate the GSNO reactivity and the NO release kinetics. Cyclodextrins (CDs) are host molecules that are typically used to encapsulate hydrophobic guest molecules into their hydrophobic cavities. However, we found that CDs form inclusion complexes with GSNO, an extremely hydrophilic molecule with a solubility of over 1 M at physiological pH. More interestingly, the host-guest complexation reduces the decomposition reactivity of GSNO in the order of alpha CD > gamma CD > hydroxypropyl beta CD. The lifetime of 0.1 M GSNO is increased to up to 15 days in the presence of CDs at 37 degree, which is more than twice the lifetime of free GSNO. Quantum chemistry calculations indicate that GSNO in alpha CD undergoes a conformational change that significantly reduces the S-NO bond distance and increases its stability. The calculated S-NO bond dissociation enthalpies of free and complexed GSNO well agree with the experimentally observed GSNO decomposition kinetics. The NO release from GSNO-CD solutions, compared to GSNO solutions, has suppressed initial bursts and extended durations, enhancing the safety and efficacy of NO-based therapies and device protections. In an example application as an anti-infective lock solution for intravascular catheters, the GSNO-alpha CD solution exhibits potent antibacterial activities for both planktonic and biofilm bacteria, both intraluminal and extraluminal environments, both prevention and treatment of infections, and against multiple bacterial strains including a multidrug-resistant strain. In addition to solutions, the inclusion complexation also enables the preparation of GSNO hydrogels with enhanced stability and improved antibacterial efficacy. Since methods to suppress and control the GSNO decomposition rate are rare, this supramolecular strategy provides new opportunities for the formulation and application of this natural NO donor.

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“…Antiviral and antibacterial activity has been demonstrated against many common causes of respiratory, gastrointestinal and soft-tissue infections; of relevance here, NO and phosphodiesterase 5-inhibitors (which maintain cyclic guanosine monophosphate levels, NO's second messenger) have antiviral effects against influenza [7,8] and coronaviruses such as SARS-CoV-2 [9,10]. A recent human trial showed that a NO-nasal spray accelerated nasal SARS-CoV-2 viral clearance [11]. Endogenous NO is made from dietary amino acids (L-arginine and L-citrulline) and nitrate [5].…”

Section: Introductionmentioning

confidence: 99%

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial

Bath

Skinner²,

Bath³

et al. 2022

Eur Geriatr Med

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Purpose Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro. We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents. Methods We performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary nitrate, and ordinal infection/clinical events. Results Of 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7–12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18–175] v 18 [10–50] mg/L, difference 25 [0–90]. Data paucity precluded clinical between-group comparisons; the outcome distribution was as follows: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common. Conclusions Recruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary nitrate. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. Trial Registration ISRCTN51124684. Application date 7/12/2020; assignment date 13/1/2021.

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SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial

Cited by 26 publications

References 18 publications

Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Inclusion Complexation of S-Nitrosoglutathione for Sustained Nitric Oxide Release from Catheter Surfaces: A Strategy to Prevent and Treat Device-Associated Infections

Inclusion Complexation of S-Nitrosoglutathione for Sustained NO Release and Reduced Device Infection

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial

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