The phosphodiesterase-4 inhibitor roflumilast impacts Schistosoma mansoni ovipositing in vitro but displays only modest antischistosomal activity in vivo
Copyright © 2019 Elsevier Inc. All rights reserved..
Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:208 |
|---|---|
| Enthalten in: |
Experimental parasitology - 208(2020) vom: 17. Jan., Seite 107793 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Botros, Sanaa S [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.12.2019 Date Revised 23.12.2019 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.exppara.2019.107793 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM303157046 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM303157046 | ||
| 003 | DE-627 | ||
| 005 | 20231225112235.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.exppara.2019.107793 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1010.xml |
| 035 | |a (DE-627)NLM303157046 | ||
| 035 | |a (NLM)31711973 | ||
| 035 | |a (PII)S0014-4894(19)30377-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Botros, Sanaa S |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The phosphodiesterase-4 inhibitor roflumilast impacts Schistosoma mansoni ovipositing in vitro but displays only modest antischistosomal activity in vivo |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.12.2019 | ||
| 500 | |a Date Revised 23.12.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a Praziquantel (PZQ) is the sole drug used to treat schistosomiasis, and the probability of developing resistance is growing the longer it is relied upon, justifying the search for alternatives. Phosphodiesterases (PDEs), particularly the PDE4 family, have attracted considerable attention as drug targets, including in Schistosoma mansoni, and especially SmPDE4A. This study investigates the potential antischistosomal activity of human PDE4 and potent SmPDE4A inhibitor roflumilast, either alone or combined with PZQ. In vitro, roflumilast resulted in a significant, concentration-dependent reduction in egg production but not of worm viability. In vitro exposure to roflumilast in combination with a low concentration of PZQ was less effective than PZQ alone, pointing to antagonism. S. mansoni-infected mice treated with roflumilast showed significant reductions in worm burden (27%) as well as hepatic and intestinal egg burdens (~28%) two weeks post treatment. Scanning EM of worms isolated from roflumilast-treated and untreated mice did not reveal noticeable changes to their tegument. S. mansoni-infected mice treated with a fixed dosage of roflumilast and a variable dosage of PZQ resulted in a higher reduction in worm burden, reduced hepatic egg counts, absence of immature eggs and a marked increase in dead eggs, compared to PZQ alone. However, the combination resulted in increased animal mortality, probably attributable to pharmacodynamic interactions between the two drugs. Although this study marks the first report of in vivo antischistosomal potential by a PDE inhibitor, an important proof of concept, we conclude that the antischistosomal effects of roflumilast are insufficient to warrant further development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Drug discovery | |
| 650 | 4 | |a Hepatic granuloma | |
| 650 | 4 | |a Mouse model | |
| 650 | 4 | |a PDE4 | |
| 650 | 4 | |a Phosphodiesterase | |
| 650 | 4 | |a Roflumilast | |
| 650 | 4 | |a Schistosoma mansoni | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Anthelmintics |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Cyclopropanes |2 NLM | |
| 650 | 7 | |a Phosphodiesterase 4 Inhibitors |2 NLM | |
| 650 | 7 | |a Roflumilast |2 NLM | |
| 650 | 7 | |a 0P6C6ZOP5U |2 NLM | |
| 650 | 7 | |a Praziquantel |2 NLM | |
| 650 | 7 | |a 6490C9U457 |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 1 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 700 | 1 | |a El-Lakkany, Naglaa M |e verfasserin |4 aut | |
| 700 | 1 | |a Seif El-Din, Sayed H |e verfasserin |4 aut | |
| 700 | 1 | |a William, Samia |e verfasserin |4 aut | |
| 700 | 1 | |a Sabra, Abdel-Nasser |e verfasserin |4 aut | |
| 700 | 1 | |a Hammam, Olfat A |e verfasserin |4 aut | |
| 700 | 1 | |a de Koning, Harry P |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Experimental parasitology |d 1953 |g 208(2020) vom: 17. Jan., Seite 107793 |w (DE-627)NLM000040436 |x 1090-2449 |7 nnns |
| 773 | 1 | 8 | |g volume:208 |g year:2020 |g day:17 |g month:01 |g pages:107793 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.exppara.2019.107793 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 208 |j 2020 |b 17 |c 01 |h 107793 | ||