scholarly journals Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025)

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Laurent Softic ◽  
Rozenn Brillet ◽  
François Berry ◽  
Nazim Ahnou ◽  
Quentin Nevers ◽  
...  
Keyword(s):  
Life Cycle ◽  
Effective Concentration ◽  
Dependent Manner ◽  
Phase 2 ◽  
Proof Of Concept ◽  
Phase 2 Trial ◽  
Dose Dependent ◽  
Cyclophilin Inhibitor

ABSTRACT Cyclophilins play a key role in the life cycle of coronaviruses. Alisporivir (Debio 025) is a nonimmunosuppressive analogue of cyclosporine with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in Vero E6 cells, with a 50% effective concentration (EC50) of 0.46 ± 0.04 μM. Alisporivir inhibited a postentry step of the SARS-CoV-2 life cycle. These results justify rapidly conducting a proof-of-concept phase 2 trial with alisporivir in patients with SARS-CoV-2 infection.

scholarly journals Assessing the effectiveness of oxathiapiprolin towards Phytophthora agathidicida, the causal agent of kauri dieback disease

FEMS Microbes ◽  
2021 ◽  
Author(s):  
Randy F Lacey ◽  
Michael J Fairhurst ◽  
Kaitlyn J Daley ◽  
Te Amohaere Ngata-Aerengamate ◽  
Haileigh R Patterson ◽  
...  
Keyword(s):  
Life Cycle ◽  
New Zealand ◽  
Mycelial Growth ◽  
Phytophthora Species ◽  
Effective Concentration ◽  
Dependent Manner ◽  
Life Cycle Stages ◽  
Leaf Infection ◽  
Dieback Disease ◽  
Dose Dependent

Abstract Phytophthora species cause disease and devastation of plants in ecological and horticultural settings worldwide. A recently identified species, P. agathidicida, infects and ultimately kills the treasured kauri trees (Agathis australis) that are endemic to New Zealand. Currently there are few options for managing kauri dieback disease. In this study, we sought to assess the toxicity of the oomycide oxathiapiprolin against several life cycle stages of two geographically distinct P. agathidicida isolates. The effective concentration to inhibit 50% of mycelial growth (EC50) was determined to be approximately 0.1 ng/ml, indicating that P. agathidicida mycelia are more sensitive to oxathiapiprolin than those from most other Phytophthora species that have been studied. Oxathiapiprolin was also highly effective at inhibiting the germination of zoospores (EC50 = 2–9 ng/ml for the two isolates) and oospores (complete inhibition at 100 ng/ml). In addition, oxathiapiprolin delayed the onset of detached kauri leaf infection in a dose-dependent manner. Collectively, the results presented here highlight the significant potential of oxathiapiprolin as a tool to aid in the control of kauri dieback disease.

scholarly journals Changes in Adrenal and Gonadal Androgens After 14-Day Treatment With CRF1 Receptor Antagonist, Crinecerfont (NBI-74788), in Men With Classic 21-Hydroxylase Deficiency

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A78-A78
Author(s):  
Xin He ◽  
Kyriakie Sarafoglou ◽  
Patricia Y Fechner ◽  
Maria George Vogiatzi ◽  
Erik Allen Imel ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Dependent Manner ◽  
Phase 2 ◽  
Hydroxylase Deficiency ◽  
Crf1 Receptor ◽  
Phase 2 Trial ◽  
Crf1 Receptor Antagonist ◽  
21 Hydroxylase Deficiency ◽  
The Impact ◽  
Dose Dependent

Abstract Background: Congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) causes cortisol insufficiency and androgen excess. A phase 2 trial of crinecerfont, a CRF1 receptor antagonist, in 18 adults with 21OHD showed prominent decreases in ACTH, 17-hydroxyprogesterone, and androstenedione (A4), and in women, testosterone (T), after 14 days of treatment. In men with 21OHD, T derives from both adrenals and testes; in poor disease control, A4/T ratio is elevated due to disproportionately increased adrenal A4 production and decreased testicular T production. We sought to determine the impact of crinecerfont on both adrenal and gonadal androgen production in men with 21OHD in this phase 2 trial. Methods: A4 and T data were analyzed for 7 men who completed 1 or more of 4 oral dosing regimens: Cohort 1, 50 mg QHS, n=4; Cohort 2, 100 mg QHS, n=2; Cohort 3, 100 mg QPM, n=5; and Cohort 4, 100 mg BID, n=3 (14 total treatment periods). Mean 0600-1000 4-hour morning window (M4hMW) and mean 24-hour (M24h) A4, T, and A4/T ratios were analyzed from serial serum samples at baseline and on day 15. Results: Dose-dependent reductions in M4hMW A4 were observed [median (range)] in men, consistent with previously presented data in all subjects:Cohort 1: -21% (-84 to -12%);Cohort 2: -37% (-51% to -23%);Cohort 3: -43% (-85% to +140%);Cohort 4: -62% (-90% to -33%). In contrast, M4hMW T showed inconsistent changes [median (range)]: Cohort 1: +18% (-40% to +82%);Cohort 2: -4% (-4.3% to -3.8%);Cohort 3: +9% (-11 to +24%);Cohort 4: +9% (-3% to +27%). Thus, M4hMW A4/T ratios decreased with dose. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 0.9 (0.3–2.6), 0.6 (0.1–2.1), -26% (-91% to +23%);Cohort 2: 5.0 (4.8–5.2), 3.3 (2.5–4.2), -35% (-49% to -20%);Cohort 3: 0.6 (0.1–6.9), 0.3 (0.1–2.7), -54% (-85% to +178%);Cohort 4: 3.9 (0.6–5.9), 0.4 (0.3–2.1), -65% (-92% to -31%). M24h A4/T ratios similarly declined in all cohorts. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 1.0 (0.3–2.3), 0.4 (0.1–1.9), -33% (-92% to +2%);Cohort 2: 4.3 (3.8–4.9), 2.7 (2.4–3.0), -36% (-51% to -22%);Cohort 3: 0.5 (0.1–4.7), 0.4 (0.1–2.4), -59% (-78% to +310%);Cohort 4: 3.2 (0.4–4.1), 0.4 (0.3–1.7), -58% (-89% to -31%). Conclusions: Following crinecerfont therapy, A4 and A4/T decreased in a dose-dependent manner in men with 21OHD. In contrast to reductions in T observed in women with 21OHD, T did not change consistently and rose in some men. Preserved T values despite marked A4 reductions suggests testicular T production increased during crinecerfont therapy, perhaps due to release of gonadotropin suppression from adrenal-derived androgens. Long term studies are needed to determine if crinecerfont treatment improves additional measures of testicular function in men with 21OHD. Reference: RJ Auchus, et al. J Endocr Soc 2020;4(Suppl 1):OR25-03.

Abstract 16955: Effects of Evolocumab (AMG 145) as a Monotherapy or in Combination with Statins on Lipoprotein Particles and Subclasses

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ren Xu ◽  
Matt Peach ◽  
Michael Tracy ◽  
Lisa Hamilton ◽  
Stephen Djedjos ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Dependent Manner ◽  
Phase 2 ◽  
P Values ◽  
Lipoprotein Particles ◽  
Treatment Regimens ◽  
Phase 2 Study ◽  
Before And After ◽  
Phase 1B ◽  
Dose Dependent

Background: Evolocumab (AMG 145) reduces LDL-C alone or in combination with statins. We evaluated the effect of evolocumab on lipoprotein particles from subjects receiving evolocumab as monotherapy or combined with statins using biomarker samples collected from 2 clinical studies. Methods: Exploratory biomarker samples, taken before and after evolocumab treatment from a phase 1b study evaluating evolocumab combined with statins in hypercholesterolemic (HCL) subjects and from a phase 2 study evaluating evolocumab as a monotherapy in HCL subjects, were analyzed by NMR at LipoScience, Inc. Lipoprotein particle concentrations and size were determined using the LP-3 module. Results: Evolocumab alone or in combination with statins significantly reduced total, small, and large LDL-P in a dose-dependent manner. As shown in the table, evolocumab monotherapy reduced total LDL-P by 45% and 54%, small LDL-P by 36% and 35%, and large LDL-P by 68% and 84%, after 140 mg and 420 mg doses, respectively. LDL-P values were reduced slightly less than LDL-C (52% at 140 mg and 62% at 420 mg), but LDL-P reductions were similar to those seen for ApoB. IDL-P, total VLDL-P, and small VLDL-P were also reduced. Total HDL-P increased, primarily due to increases in large HDL-P. Similar results were obtained when evolocumab was given combined with statins, but with greater reductions in total, small, and large LDL-P. Notably, greater reductions in LDL-P or LDL-C were correlated with higher concentrations of total LDL-P, small LDL-P, triglycerides, smaller LDL size, and lower HDL-C at baseline. Conclusion: Evolocumab either alone or in combination with statins affected lipoprotein particles similarly. In both treatment regimens, LDL-C and total LDL-P were significantly reduced and large LDL-P were reduced, on average, to a greater extent than small LDL-P. Total LDL-P was reduced to a lesser extent than LDL-C. Additionally, reductions in VLDL-P and IDL-P were observed along with increases in HDL-P.

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