The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease

Hatzelmann, Armin; Morcillo, Esteban J.; Lungarella, Giuseppe; Adnot, Serge; Sanjar, Shahin; Beume, Rolf; Schudt, Christian; Tenor, Hermann

doi:10.1016/j.pupt.2010.03.011

Cited by 279 publications

(256 citation statements)

References 229 publications

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“…Nevertheless, treatment of Cln3 Δex7/8 animals with 5mg/kg/day roflumilast did significantly improve motor performance compared to vehicle‐treated Cln3 Δex7/8 mice. Compared to rolipram, the beneficial effects of roflumilast on motor activity were not observed until 3 months of treatment, which may be explained by the lower blood–brain barrier permeability of roflumilast 24, 25…”

Section: Resultsmentioning

confidence: 96%

“…In addition to augmenting glutamate transporter expression, it is also possible that the beneficial effects of PDE4 inhibitors in Cln3 Δex7/8 mice may be mediated, in part, by dampening neuroinflammatory responses that are suggested to occur in JNCL,6, 7, 8, 53 because PDE4 inhibitors have been shown to reduce inflammation in other neurological conditions 17, 18, 19, 24, 25, 26. The ability of PDE4 inhibitors to significantly reduce astrocyte and microglial activation in Cln3 Δex7/8 mice supports this tenet.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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ObjectiveJuvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase‐4 (PDE4) inhibitors (rolipram, roflumilast, and PF‐06266047) could mitigate behavioral deficits and cell‐specific pathology in the Cln3Δex7/8 mouse model of JNCL.MethodsIn a randomized, blinded study, wild‐type (WT) and Cln3Δex7/8 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal‐associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3Δex7/8 animals.ResultscAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF‐06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis.InterpretationThese studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Aldrich

Bosch

Fallet

et al. 2016

Annals of Neurology

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“…PDE4 selectively hydrolyses and inactivates cAMP. Its function in inflammatory cells was intensively studied [2] and research into PDE4 inhibitors has focused primarily on inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD) [3]. Recent evidence suggests that PDE4 plays an essential role in glucose and fat metabolism [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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Aims/hypothesis The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects. Methods Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA 1c , blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.Results Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5-and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA 1c by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolininduced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. Conclusions/interpretation Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.

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“…Both roflumilast and N-oxide are mainly excreted via the urine. There are no major drug interactions reported between roflumilast and other (COPD-related) pharmacological treatments [37,38].…”

Section: Roflumilast: Pharmacokinetics Clinical Efficacy From Phase mentioning

confidence: 99%

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

Diamant

Spina

2011

Pulmonary Pharmacology & Therapeutics

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SummaryRoflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed. keywords: PDE4-inhibitor, roflumilast, clinical trials, chronic obstructive airways disease 3

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The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease

Cited by 279 publications

References 229 publications

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

Efficacy of phosphodiesterase‐4 inhibitors in juvenile Batten disease (CLN3)

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease

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