scholarly journals Development of a novel, pan-variant aerosol intervention for COVID-19

2021 ◽  
Author(s):  
Robert H. Shoemaker ◽  
Reynold A Panettieri ◽  
Steven K Libutti ◽  
Howard S Hochster ◽  
Norman R Watts ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Range ◽  
Binding Activity ◽  
Lung Damage ◽  
Repeat Dose ◽  
Virus Binding ◽  
Range Finding ◽  
Viral Binding ◽  
Effective Interventions ◽  
Spread Of Infection

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants.

Safety and pharmacokinetics of a kinin B1 receptor peptide agonist produced with different counter-ions

2016 ◽  
Vol 397 (4) ◽  
pp. 365-372
Author(s):  
Martin Savard ◽  
Jérôme Côté ◽  
Luc Tremblay ◽  
Witold Neugebauer ◽  
Domenico Regoli ◽  
...  
Keyword(s):  
Clinical Chemistry ◽  
Dose Range ◽  
Clinical Pathology ◽  
Maximum Tolerated Dose ◽  
Tolerability Profile ◽  
Repeat Dose ◽  
Range Finding ◽  
B1 Receptor ◽  
Kinin B1 Receptor ◽  
Acetate Form

Abstract Several studies have shown the potential therapeutic utility of kinin B1 receptor (B1R) peptide agonists in neurological and ischemic cardiovascular diseases and brain cancer. Preclinical safety studies are a prerequisite for further drug development. The objectives of this study were to determine the acute toxicity and pharmacokinetics of the peptide B1R agonist, SarLys[dPhe8]desArg9-bradykinin (NG29), as trifluoroacetate (TFacetate) or acetate salt form, following intravenous injection in rats. A maximum tolerated dose (MTD) of NG29-TFacetate was established at 75 mg/kg from the results of a dose range-finding study (up to 200 mg/kg). The short-term (4-day) repeat-dose toxicity study of NG29, using its MTD value, showed that NG29-acetate exhibited minimal non-adverse clinical pathology changes in hematology, coagulation, clinical chemistry and urine parameters and severe kidney histopathological changes characterized by renal tubular degeneration. No such effects were observed with NG29-TFacetate. At the injection site, NG29-TFacetate was considered to be more locally irritating when compared to the acetate form. The extent of exposure and half-life values of NG29-TFacetate were comparable to the acetate form (AUC0–α of 10.2 mg/l*h vs. 9.9 mg/l*h; T1/2 of 2.3 h vs. 2.4 h). This study shows that in rats NG29-TFacetate exhibits a superior tolerability profile compared with the peptide acetate form.

Dried Blood Spot Analysis of Donepezil in Support of a GLP 3-month Dose-Range Finding Study in Rats

2012 ◽  
Vol 31 (4) ◽  
pp. 337-347 ◽  
Author(s):  
Susan R. Meier-Davis ◽  
Min Meng ◽  
Weiwei Yuan ◽  
Lisa Diehl ◽  
Fatima M. Arjmand ◽  
...  
Keyword(s):  
Dose Range ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Dried Blood Spot ◽  
Topical Formulation ◽  
Carcinogenicity Study ◽  
Range Finding ◽  
Donepezil Hydrochloride ◽  
Blood Spot

Donepezil hydrochloride is a reversible acetyl cholinesterase inhibitor approved for Alzheimer disease treatment. As an alternate therapy, a donepezil hydrochloride transdermal patch is in development. Recommended nonclinical safety studies include a 3-month Good Laboratory Practice (GLP) dose-range finding (DRF) study prior to conducting the 2-year dermal carcinogenicity study in rats. Demonstration of systemic exposure is necessary to interpret the in vivo data. Previous nonclinical reports supporting oral dosing have utilized liquid chromatography tandem mass spectrometry (LC/MS/MS) to quantify donepezil concentrations in plasma. Smaller species with limited blood volumes do not allow serial sampling to derive the full pharmacokinetic profile from a single animal. Therefore, the option of another analytical method requiring decreased sample volumes is desirable as it would decrease the required number of animals while obtaining the complete profile. The dried blood spot (DBS) technique allows drug level measurement from a few microliters; however, the method is still not widely utilized in GLP studies. Because donepezil plasma levels are known by the oral route, DBS was used to bridge the previous oral data and to support a 13-week GLP DRF study for repeated topical application in rats, comparing oral administration with 4 topical formulations. The DBS method was validated and demonstrated robustness and reproducibility for application to the DRF study. The assay results were comparable to a previously reported plasma LC/MS/MS assay-derived pharmacokinetic profile and provided justification for selection of the topical formulation and dose levels for the subsequent dermal carcinogenicity study.

Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

2004 ◽  
Vol 23 (3) ◽  
pp. 179-189 ◽  
Author(s):  
Sandhya Ramanathan-Girish ◽  
Paul Catz ◽  
Moire R. Creek ◽  
Benjamin Wu ◽  
David Thomas ◽  
...  
Keyword(s):  
Oral Dose ◽  
Oral Administration ◽  
Antimalarial Drug ◽  
Dose Range ◽  
Plasmodium Species ◽  
Repeat Dose ◽  
Nonlinear Kinetics ◽  
Dose Administration ◽  
Blood Concentrations ◽  
Cynomolgus Macaques

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats ( n = 4 /sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved Cmax after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and Cmax values following single oral dose administration were not dose proportional; the Cmax value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. MonodesethylAQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding Cmax values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism ofAQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

scholarly journals Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy

2020 ◽  
Vol 31 (13-14) ◽  
pp. 743-755 ◽  
Author(s):  
Chunjuan Song ◽  
Valérie L. Dufour ◽  
Artur V. Cideciyan ◽  
Guo-Jie Ye ◽  
Malgorzata Swider ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Dose Range ◽  
Canine Model ◽  
Range Finding

Two Procedures for the Prediction of Acute Toxicity (LD50) from Cytotoxicity Data

1992 ◽  
Vol 20 (1) ◽  
pp. 40-49 ◽  
Author(s):  
Willi Halle ◽  
Horst Spielmann
Keyword(s):  
Linear Regression ◽  
Acute Toxicity ◽  
Correlation Coefficient ◽  
Mammalian Cell ◽  
Wide Spectrum ◽  
Dose Range ◽  
Linear Regression Analysis ◽  
Range Finding ◽  
Mammalian Cell Lines ◽  
Ic50 Values

Single linear regression analysis was used to characterise the relationship between cytotoxicity in a variety of mammalian cell culture systems and acute oral toxicity (LD50) in experimental animals. The following results were obtained. Firstly, in a cytotoxicity assay using the calf aortic endothelial cell line BKEz-7, IC50 values determined for 44 chemicals in culture showed significant correlation with the oral LD50 values for rat and mouse (computed correlation coefficient r=0.546). After eliminating three chemicals that were characterised by extreme lethality indices (LI = IC50/LD50), the correlation coefficient of the remaining 41 chemicals increased to a value of r=0.728. By using the linear regression model for these 41 chemicals, the oral LD50 for rat and mouse can be predicted correctly from the IC50 values for 83% of substances from a variety of chemical substance classes within a range of approximately one order of magnitude of dosage unit of LD50 for rat and mouse. Secondly, the mean IC50 values (IC50x¯) determined as the geometrical mean of two or more IC50 values per substance, which were generated in a wide spectrum of mammalian cell lines and collected in a “Registry of Cytotoxicity” (RC), gave similar results (r=0.644). Likewise, with the aid of this method, the oral LD50 for rat and mouse can be predicted for 74% of non-selected chemicals from structurally-different classes in the same dosage range, e.g., 1–25 millimoles per kg body weight. The prediction of LD50 values from in vitro cytotoxicity data may permit the calculation of a more precise dose range-finding and offers a new way for reducing the number of animals in acute toxicity testing.

scholarly journals Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

2017 ◽  
Vol 36 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Madhav G. Paranjpe ◽  
Jessica Belich ◽  
Tom J. Vidmar ◽  
Reem H. Elbekai ◽  
Marie McKeon ◽  
...  
Keyword(s):  
Selection Process ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Dose Selection ◽  
Range Finding ◽  
Body Weights ◽  
Vehicle Test ◽  
High Doses ◽  
Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies

2016 ◽  
Vol 43 (9) ◽  
pp. 1637-1642 ◽  
Author(s):  
Robin L. Thurmond ◽  
Andrew Greenspan ◽  
Waldemar Radziszewski ◽  
Xie L. Xu ◽  
Ye Miao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Receptor Antagonist ◽  
Active Rheumatoid Arthritis ◽  
Dose Range ◽  
Joint Disease ◽  
Double Blind ◽  
Once Daily ◽  
Double Blind Placebo ◽  
Range Finding ◽  
Phase Ii Studies

Objective.To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).Methods.In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range–finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP).Results.Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.Conclusion.Toreforant was not effective in phase IIb testing.

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