Pharmacokinetics and Tolerability of a New Manidipine and Delapril Fixed Oral Combination in Young and Elderly Subjects

Stockis, Armel; Bruyn, Steven De; Gengler, Christophe; Goethals, F.; Lens, Simone; Poli, Gianluigi; Acerbi, Daniela

doi:10.1055/s-0031-1297149

Cited by 3 publications

(1 citation statement)

References 3 publications

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“…cells CC 50 (µM) Synergy score with remdesivir (δ) SARS-CoV-2 EC50 (µM) Uninf. cells CC50 (µM) Remdesivir (GS--5734) RdRP inhibitor Emergency FDA registration 5 µM (human oral) 1 33 0.127 (0.123)* 9.97 (9.67)* n/a 0.606 (0.444)* > 30 (> 30)* Halofantrine HCl Antimalarial; hemozoin inhibitor Registered 1 µM (human oral) 58 34 , 35 0.33 18.71 −3.51 > 8.470 > 22.59 Manidipine Ca 2+ -channel blocker related to amlodipine Registered 10 nM (human, oral) 3 36 , 37 6.89 > 17.07 −4.73 5.481 > 30 Nelfinavir mesylate HIV protease inhibitor Registered 17 µM (human oral) 7 38 , 39 > 8.643 > 18.02 −1.23 0.361 > 9.40 Simeprevir Hepatitis C NS3/4A protease inhibitor Registered 32 µM (human oral) 16 40 , 41 7.88 > 22.17 −0.67 7.704 > 22.39 Avoralstat Plasma kallikrein (KLKB1) inhibitor Phase III 364 nM (human, oral) 14 42 > 9.6 > 40 n/d 0.387 > 30 Bardoxolone methyl Antiinflammatory; NFkB inhibit...…”

Section: Resultsmentioning

confidence: 99%

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

et al. 2021

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The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

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Section: Resultsmentioning

confidence: 99%

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

et al. 2021

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Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19

Bakowski

Beutler

Chen

et al. 2020

Preprint

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The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.

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Delapril/Manidipine

McCormack¹,

Keating²

2006

Drugs

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Delapril/manidipine 30 mg/10 mg is a new oral, once-daily, fixed combination of an ACE inhibitor and a dihydropyridine calcium-channel antagonist for the treatment of essential hypertension. In a dose-finding study in 400 patients with mild to moderate hypertension, delapril/manidipine 30mg/10mg once daily produced the greatest reduction in blood pressure (BP) of the combinations tested. Delapril/manidipine 30mg/10mg once daily for 6 weeks reduced systolic BP (SBP)/diastolic BP (DBP) by 15/13mm Hg. In nonresponders to monotherapy with delapril (n = 155) or manidipine (n = 152), delapril/manidipine 30mg/10mg once daily for 12 weeks reduced mean SBP/DBP by 16/11mm Hg and 16/10mm Hg, respectively. Delapril/manidipine 30mg/10mg once daily for 12 weeks in patients with mild to moderate hypertension (n = 131) demonstrated significantly greater antihypertensive efficacy than monotherapy with manidipine 10mg once daily (n = 134) or delapril 15mg twice daily (n = 136). Mean SBP/DBP reductions from baseline were 19/14, 15/11 and 14/10mm Hg, respectively. After 50 weeks of therapy with delapril/manidipine 30mg/10mg once daily, mean SBP/DBP was reduced by 22/14mm Hg in patients with mild to moderate hypertension (n = 309). Delapril/manidipine 30mg/10mg once daily was generally well tolerated. The incidence and nature of adverse events were similar to those observed in recipients of monotherapy with the individual agents. Combination therapy was associated with less ankle oedema than manidipine monotherapy.

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Pharmacokinetics and Tolerability of a New Manidipine and Delapril Fixed Oral Combination in Young and Elderly Subjects

Cited by 3 publications

References 3 publications

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions

Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19

Delapril/Manidipine

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