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.

scholarly journals OR25-03 The Effects of Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, on Adrenal Androgens and Precursors in Patients with Classic Congenital Adrenal Hyperplasia: Results from A Multiple-Dose Phase 2 Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Richard J Auchus ◽  
Kyriakie Sarafoglou ◽  
Patricia Y Fechner ◽  
Maria Vogiatzi ◽  
Nagdeep Giri ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Multiple Dose ◽  
Phase 2 ◽  
Adrenal Hyperplasia ◽  
Plasma Acth ◽  
Adrenal Androgens ◽  
Crf1 Receptor ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Phase 2 Study ◽  
Crf1 Receptor Antagonist

Abstract Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD CAH) is a rare autosomal recessive disease that results in impaired cortisol synthesis and excess androgen production. Compounds that inhibit adrenocorticotropic hormone (ACTH) release could reduce adrenal androgen production and thus the amounts of exogenous glucocorticoids needed to decrease these androgen levels. This study evaluated the effect of crinecerfont (NBI-74788), a novel, non-steroidal, and selective corticotropin-releasing factor-1 (CRF1) receptor antagonist on adrenal androgens and precursors in adults with 21OHD CAH. Methods: This open-label, multiple-dose study enrolled men and women (18–50 years old) with 21OHD CAH. A sequential-cohort design evaluated 4 crinecerfont oral dosing regimens: 50 mg QHS (Cohort 1); 100 mg QHS (Cohort 2); 100 mg QD (Cohort 3); and 100 mg alternative dosing (Cohort 4). Each regimen was administered for 14 consecutive days. ACTH, 17-hydroxy-progesterone (17OHP), and androstenedione (A4) were measured serially over a 24-hour period, at baseline and after 14 days of dosing. Results: Analyses included 23 participants: Cohort 1 (4 women, 4 men: mean age 31.1 years); Cohort 2 (5 women, 2 men: mean age 32.9 years); and Cohort 3 (3 women, 5 men: mean age 30.9 years). Cohort 4 is ongoing. At baseline, median plasma ACTH, serum 17OHP, and serum A4 levels were as follows: Cohort 1 (ACTH, 151 pg/mL; 17OHP, 5352 ng/dL; A4, 270 ng/dL); Cohort 2 (ACTH, 232 pg/mL; 17OHP, 12821 ng/dL; A4, 597 ng/dL); and Cohort 3 (ACTH, 470 pg/mL; 17OHP, 6451 ng/dL; A4, 299 ng/dL). After 14 days of once-daily crinecerfont 50 mg, Cohort 1 patients had median percent reductions from baseline in plasma ACTH (-54%), serum 17OHP (-60%), and serum A4 (-21%). Median percent reductions were generally larger with 100 mg in Cohort 2 (ACTH, -67%; 17OHP, -75%; A4, -47%) and Cohort 3 (ACTH, -69%; 17OHP, -55%; A4, -43%), consistent with a dose-related response. Adverse events were mostly mild; no clinically significant findings from routine laboratory tests, vital signs, or electrocardiograms were noted. Conclusions: Results of this Phase 2 study of crinecerfont, a novel, orally administered, selective CRF1-receptor antagonist, indicated clinically meaningful reductions of elevated ACTH, 17OHP, and A4 in adults with 21OHD CAH after 14 days of treatment. Further studies are warranted to evaluate the effects of chronic crinecerfont therapy on maintenance of adrenal steroid production, clinical endpoints of disordered steroidogenesis, and reductions in GC exposure in both adult and pediatric patients with 21OHD CAH.

Dose-dependent effects of the CRF1 receptor antagonist R317573 on regional brain activity in healthy male subjects

2009 ◽  
Vol 208 (1) ◽  
pp. 109-119 ◽  
Author(s):  
Mark E. Schmidt ◽  
Randolph D. Andrews ◽  
Peter van der Ark ◽  
Terry Brown ◽  
Erik Mannaert ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Brain Activity ◽  
Healthy Male ◽  
Crf1 Receptor ◽  
Regional Brain ◽  
Crf1 Receptor Antagonist ◽  
Regional Brain Activity ◽  
Dose Dependent ◽  
Male Subjects

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 Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1156
Author(s):  
Madelaine Sugasti-Salazar ◽  
Yessica Y. Llamas-González ◽  
Dalkiria Campos ◽  
José González-Santamaría
Keyword(s):  
Protein Expression ◽  
Hela Cells ◽  
Plaque Assay ◽  
Dermal Fibroblasts ◽  
Dependent Manner ◽  
Human Dermal Fibroblasts ◽  
Mitogen Activated Protein ◽  
Mayaro Virus ◽  
The Impact ◽  
Dose Dependent

Mayaro virus (MAYV) hijacks the host’s cell machinery to effectively replicate. The mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK1/2 have emerged as crucial cellular factors implicated in different stages of the viral cycle. However, whether MAYV uses these MAPKs to competently replicate has not yet been determined. The aim of this study was to evaluate the impact of MAPK inhibition on MAYV replication using primary human dermal fibroblasts (HDFs) and HeLa cells. Viral yields in supernatants from MAYV-infected cells treated or untreated with inhibitors SB203580, SP600125, U0126, or Losmapimod were quantified using plaque assay. Additionally, viral protein expression was analyzed using immunoblot and immunofluorescence. Knockdown of p38⍺/p38β isoforms was performed in HDFs using the PROTACs molecule NR-7h. Our data demonstrated that HDFs are highly susceptible to MAYV infection. SB203580, a p38 inhibitor, reduced MAYV replication in a dose-dependent manner in both HDFs and HeLa cells. Additionally, SB203580 significantly decreased viral E1 protein expression. Similarly, knockdown or inhibition of p38⍺/p38β isoforms with NR-7h or Losmapimod, respectively, affected MAYV replication in a dose-dependent manner. Collectively, these findings suggest that p38 could play an important role in MAYV replication and could serve as a therapeutic target to control MAYV infection.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

2017 ◽  
Vol 25 (5) ◽  
pp. 1556-1570 ◽  
Author(s):  
Michiyo Mochizuki ◽  
Takuto Kojima ◽  
Katsumi Kobayashi ◽  
Etsuo Kotani ◽  
Yuji Ishichi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Crf1 Receptor ◽  
Crf1 Receptor Antagonist

scholarly journals Comparison of Different Methods for Extracting the Astaxanthin from Haematococcus pluvialis: Chemical Composition and Biological Activity

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3569
Author(s):  
Yicheng Tan ◽  
Zhang Ye ◽  
Mansheng Wang ◽  
Muhammad Faisal Manzoor ◽  
Rana Muhammad Aadil ◽  
...  
Keyword(s):  
High Pressure ◽  
Biological Activity ◽  
Chemical Composition ◽  
Haematococcus Pluvialis ◽  
Activity Analysis ◽  
Cell Disruption ◽  
Dependent Manner ◽  
Dpph Activity ◽  
The Impact ◽  
Dose Dependent

In this study, the impact of different cell disruption techniques (high-pressure micro fluidization (HPMF), ionic liquids (ILs), multi-enzyme (ME), and hydrochloric acid (HCl)) on the chemical composition and biological activity of astaxanthin (AST) obtained from Haematococcus pluvialis was investigated. Results indicated that all cell disruption techniques had a significant effect on AST composition, which were confirmed by TLC and UPC2 analysis. AST recovery from HCl (HCl-AST) and ILs (ILs-AST) cell disruption techniques was dominant by free and monoesters AST, while AST recovery from HPMF (HPMF-AST) and ME (ME-AST) cell disruption techniques was composed of monoesters, diesters, and free AST. Further biological activity analysis displayed that HCl-AST showed the highest ABTS and DPPH activity, while ILs-AST showed better results against the ORAC assay. Additionally, ILs-AST exhibits a stronger anti-proliferation of HepG2 cells in a dose-dependent manner, which was ascribed to AST-induced ROS in to inhibit the proliferative of cancer cells.

A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig

1992 ◽  
Vol 72 (6) ◽  
pp. 2415-2419 ◽  
Author(s):  
J. Lotvall ◽  
W. Elwood ◽  
K. Tokuyama ◽  
T. Sakamoto ◽  
P. J. Barnes ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Evans Blue ◽  
Blue Dye ◽  
Dependent Manner ◽  
Evans Blue Dye ◽  
Plasma Exudation ◽  
Txa2 Receptor ◽  
Txa2 Receptor Antagonist ◽  
Airway Responses ◽  
Dose Dependent

Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.

Oxytocin affects apical sodium conductance in rabbit cortical collecting duct

1993 ◽  
Vol 265 (4) ◽  
pp. F487-F503 ◽  
Author(s):  
T. Inoue ◽  
M. Naruse ◽  
M. Nakayama ◽  
K. Kurokawa ◽  
T. Sato
Keyword(s):  
Receptor Antagonist ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Physiological Role ◽  
Free Calcium ◽  
Second Phase ◽  
Dependent Manner ◽  
Cortical Collecting Duct ◽  
Acetoxymethyl Ester ◽  
Dose Dependent

The physiological role of oxytocin (OT) in the kidney is still unclear, although autoradiographic data have shown the existence of OT receptors in the rat kidney. We examined the effect of OT in the microperfused rabbit cortical collecting duct (CCD) by using conventional cable analysis and microscope photometry. On addition of 10(-9) M OT to the bath, the lumen-negative transepithelial voltage (VT) transiently increased and the transepithelial resistance (RT) and the fractional resistance of the apical membrane (FRA) (1st phase) both decreased. After this initial change, the lumen-negative VT gradually decreased below its baseline level and RT and FRA (second phase) both increased. These electrical changes were dose dependent and were prevented by the addition of 10(-5) M amiloride to the lumen. Although responses to OT were not prevented by 10(-9) M arginine vasopressin (AVP) or 10(-6) M of a V1-receptor antagonist (OPC-21268) or V2-receptor antagonist (OPC-31260), they were inhibited by the addition of the specific OT antagonist des-Gly-NH2-[d(CH2)3,Tyr(Me),Thr]OVT. Additional studies of intracellular free calcium ([Ca2+]i) revealed that 10(-8)-10(-6) M OT caused an increase in [Ca2+]i in CCD in a dose-dependent manner. Also, pretreatment with 2 x 10(-8) M bis-(aminophenoxy)ethane-tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, abolished the electrical and [Ca2+]i responses to OT. Pretreatment with 5 x 10(-4) M 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) partially prevented the electrical responses to OT, thus reducing the decrease in lumen-negative VT below its basal level and the increase in RT after the 1st phase. These data show that OT affects the apical Na+ conductance of collecting duct cells through OT receptors distinct from the AVP receptors and that the effect of OT may, at least in part, be brought about by a mechanism(s) dependent on the increase in [Ca2+]i and cAMP production.

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