Inhibitory Effects of Hesperetin Derivatives on Guinea Pig Phosphodiesterases and Their Ratios Between High- and Low-Affinity Rolipram Binding

Hsu, Hsin Te; Wang, Wen Hung; Han, Cheng Ying; Chen, Chun Nan; Chen, Chi Ming; Ko, Wun-Chang

doi:10.1002/jps.23591

Cited by 7 publications

(10 citation statements)

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“…Cilomilast and roflumilast have therapeutic ratios of 1 and 3, respectively [5, 21]. Recently, roflumilast was approved by the European Commission [6] and the US FDA [4] as an add-on to bronchodilator therapy for maintenance treatment of severe COPD associated with chronic bronchitis in adults with a history of frequent exacerbations.…”

Section: Discussionmentioning

confidence: 99%

“…1) was synthesized in accordance with a previously described method [14]. The purity of HTA exceeded 98% and the structure was determined by spectral methods [4]. The reference drug, roflumilast (Daxas® film-coated tablets) was a gift from Takeda Pharmaceutical (Taipei, Taiwan).…”

Section: Methodsmentioning

confidence: 99%

“…HTA was reported to dually inhibit PDE3/4 with a therapeutic (PDE4 H /PDE4 L ) ratio of 20.8 [4], which is greater than that of roflumilast [5], a selective PDE4 inhibitor. Roflumilast was approved by the European Commission [6], and the US Food and Drug Administration (FDA) [4] as an adjunct to bronchodilator therapy for severe COPD associated with chronic bronchitis in adults with a history of frequent exacerbations. However, dual PDE3/4 inhibitors are reported to have additive or synergistic anti-inflammatory and bronchodilator effects compared to PDE3 or PDE4 inhibitors alone [7].…”

Section: Introductionmentioning

confidence: 99%

“…However, dual PDE3/4 inhibitors are reported to have additive or synergistic anti-inflammatory and bronchodilator effects compared to PDE3 or PDE4 inhibitors alone [7]. In other words, the real therapeutic ratio of dual PDE3/4 inhibitors should be greater than that reported [4]. Therefore, we were interested in investigating the suppressive effects of HTA on ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), and clarifying its potential for treating atypical asthma and COPD [8].…”

Section: Introductionmentioning

confidence: 99%

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Hesperetin-5,7,3’-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice

You

Chen

et al. 2017

BMC Pharmacol Toxicol

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BackgroundWe recently reported that hesperetin-5,7,3’-O-triacetate (HTA) dually inhibited phosphodiesterase (PDE)3/4 with a therapeutic ratio of 20.8. The application and development of PDE4 inhibitors for treating asthma or COPD are limited by their side effects, such as nausea, vomiting and gastric hypersecretion. PDE4 inhibitors were reported to reverse xylazine/ketamine-induced anesthesia in rats and triggered vomiting in ferrets. Thus the reversing effect of HTA on xylazine/ketamine-induced anesthesia in mice was studied to assess emetic effect of HTA. The aim of this study was to prove the therapeutic effect of HTA without vomiting effect at an effective dose for treating COPD.MethodsTen female BALB/c mice in each group were sensitized by ovalbumin (OVA) on days 0 and 14. On day 21, these mice were emphasized the sensitization by Freund’s complete adjuvant. Mice were challenged by 1% OVA nebulization on days 28, 29, and 30. Airway hyperresponsiveness (AHR) was assessed on day 32 in each group, using the FlexiVent system to determine airway resistance (RL) and lung dynamic compliance (Cdyn) in anesthetized ovalbumin (OVA)-sensitized and challenged mice. Each group was orally administered HTA (10 ~ 100 μmol/kg), roflumilast (1 and 5 mg/kg) or vehicles (controls) 2 h before and 6 and 24 h after OVA provocation. For comparison, sham-treated mice were challenged with saline instead of 1% OVA. The ability to reverse xylazine/ketamine-induced anesthesia by HTA or roflumilast for 3 h was determined in normal mice. We used roflumilast, a selective PDE4 inhibitor and bronchodilator for severe COPD approved by the US Food and Drug Administration, as a reference drug.ResultsIn the results, HTA (100 μmol/kg, p.o.) or roflumilast (5 mg/kg, p.o.) significantly suppressed all RL values of MCh at 0.78 ~ 25 mg/mL and enhanced Cdyn values of MCh at 3.125 ~ 25 mg/mL compared to OVA-sensitized and -challenged control mice. Orally administered 1, 3 or 10 mg/kg roflumilast, but not 30 or 100 μmol/kg HTA, significantly reversed xylazine/ketamine-induced anesthesia.ConclusionsIn contrast to roflumilast, HTA may ameliorate COPD but induce few side effects of nausea, vomiting and gastric hypersecretion at an effective dose for treating COPD, because HTA did not reverse xylazine/ketamine-induced anesthesia in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hesperetin-5,7,3’-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice

You

Chen

et al. 2017

BMC Pharmacol Toxicol

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“…The therapeutic (PDE4 H /PDE4 L ) ratio of selective PDE4 and dual PDE3/4 inhibitors for treating asthma and chronic obstructive pulmonary disease (COPD) has been established. 2,3 However, the real therapeutic ratio of dual PDE3/4 inhibitors should be greater than that reported, 3 because they are reported to have additive or synergistic effects compared to PDE3 or PDE4 inhibitors alone. 4 Synthetic hesperetin-5,7,3ʹ-O-trimethylether (HTME) dually inhibited PDE3/4 with a therapeutic (PDE4 H /PDE4 L ) ratio of 18.3 3 which is greater than that (3) of roflumilast, an orally administered selective PDE4 inhibitor.…”

Section: Introductionmentioning

confidence: 95%

<p>Hesperetin-5,7,3ʹ-O-Trimethylether Dually Inhibits Phosphodiesterase 3/4 and Methacholine-Induced Airway Hyperresponsiveness in Sensitized and Challenged Mice</p>

Shih

Wang

Chen

et al. 2020

DDDT

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Introduction: Hesperetin-5,7,3ʹ-O-trimethylether (HTME), a synthetic liposoluble hesperetin, has been reported to be a dual phosphodiesterase (PDE)3/4 inhibitor. We investigated its inhibitory effects on methacholine (MCh)-induced airway hyperresponsiveness (AHR) and its potential for treating atypical asthma and COPD. Methods: FlexiVent system was used to determine AHR in ovalbumin (OVA) sensitized and challenged mice. Determination of cytokines was performed by using mouse T helper (Th)1/Th2 cytokine CBA kits, and of total immunoglobulin (Ig)E and OVA-specific IgE using ELISA kits. The number of inflammatory cells was counted using a hemocytometer. Xylazine/ketamineinduced anesthesia was to assess nausea, vomiting, and gastric hypersecretion in these mice. Results: HTME dually and competitively inhibited PDE3/4 activities in the Lineweaver-Burk analysis. HTME (30 and 100 μmol/kg) dose-dependently and significantly decreased the airway resistance (R L) and increased lung dynamic compliance (C dyn) values induced by MCh. It significantly suppressed numbers of total inflammatory cells and neutrophils, and levels of cytokines in bronchoalveolar lavage fluid (BALF). HTME dose-dependently and significantly inhibited total and OVA-specific IgE levels in the BALF and serum. However, HTME did not influence xylazine/ketamine-induced anesthesia. Conclusion: HTME exerted anti-inflammatory and bronchodilator effects and may be useful in treating chronic obstructive pulmonary disease and allergic atypical asthma with no gastrointestinal side effects.

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Hesperetin Relaxes Depolarizing Contraction in Human Umbilical Vein by Inhibiting L-Type Ca2+ Channel

Tipcome,

Watanapa,

Ruamyod

2024

Chin. J. Integr. Med.

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Inhibitory Effects of Hesperetin Derivatives on Guinea Pig Phosphodiesterases and Their Ratios Between High- and Low-Affinity Rolipram Binding

Cited by 7 publications

References 28 publications

Hesperetin-5,7,3’-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice

Hesperetin-5,7,3’-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice

<p>Hesperetin-5,7,3ʹ-O-Trimethylether Dually Inhibits Phosphodiesterase 3/4 and Methacholine-Induced Airway Hyperresponsiveness in Sensitized and Challenged Mice</p>

Hesperetin Relaxes Depolarizing Contraction in Human Umbilical Vein by Inhibiting L-Type Ca2+ Channel

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