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Compositions and methods for treating COPD and other inflammatory conditions

A composition and compound technology, applied in the direction of biochemical equipment and methods, drug combinations, active ingredients of heterocyclic compounds, etc.

Inactive Publication Date: 2017-12-01
GEORGIA STATE UNIV RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is also clinical evidence that repeated dosing of roflumilast produces tachyphylaxis or resistance

Method used

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  • Compositions and methods for treating COPD and other inflammatory conditions
  • Compositions and methods for treating COPD and other inflammatory conditions
  • Compositions and methods for treating COPD and other inflammatory conditions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Example 1: Roflumilast works synergistically with NTHi to upregulate PDE4B2 expression in vitro and in vivo. Because the expression of PDE4 isoforms is induced by PDE4 inhibitors (Campos-Toimil et al., British Journal of Pharmacology (Br.J.Pharmacol.) 154 (1): 82-92, 2008; Dlaboga et al., Brain Research (Brain Res.), 1096(1):104-112, 2006; Giorgi et al., Behav. Brain Res. 154(1); 99-106, 2004) and PDE4B is also induced by NTHi (Komatsu et al., Nature Communication (Nat. Commun.) 4: 1684, 2013), we sought to determine whether roflumilast synergizes with NTHi to induce PDE4B expression in human airway epithelial cells (BEAS-2B cells). As shown in Figures 2A and 2B, rofluristine does synergize with NTHi to upregulate PDE4B at the mRNA level in a dose-dependent manner assessed by quantitative PCR (Q-PCR) analysis in human bronchial epithelial BEAS-2B cells Express. Similar results were also confirmed in primary normal human bronchial epithelial (NHBE) cells (Fig. 2C). We...

Embodiment 2

[0142] Example 2: PDE4B2 is required for NTHi-induced expression of pro-inflammatory mediators. We next sought to determine the role of PDE4B2 expression in NTHi-induced inflammatory responses in human airway epithelial cells. Pro-inflammatory mediators including cytokines and chemokines play a key role in the recruitment and activation of leukocytes from the circulation to the lung in airway inflammatory diseases (Donnelly and Barnes, Trends Pharmacol.Sci. , 27(10): 546-553, 2006; Le et al., Cell Mol. Immunol., 1(2): 95-104, 2004; Quint and Wedzicha, Journal of Allergy and Clinical Immunology Activation ( J. Allergy Clin. Immunol.), 119(5): 1065-1071, 2007). Airway epithelial cells are an important source of pro-inflammatory mediators induced by bacterial pathogens (Hallstrand et al., Clin. Immunol., 161(1): 1-15, 2014). We therefore first determined whether NTHi induces the expression of a number of key pro-inflammatory mediators shown to be crucial in the pathogenesis of ...

Embodiment 3

[0146]Example 3: Synergistic induction of PDE4B2 requires PKA-Cβ but not PKA-Cα. To investigate the mechanism of synergistic induction of PDE4B2, we first examined whether cAMP increased by roflumilast is involved in the synergistic induction of PDE4B2. Forskolin (FSK), a potent cAMP-elevating agent, synergized with NTHi to upregulate PDE4B2 expression, suggesting that cAMP is involved in the synergistic induction of PDE4B2 in BEAS-2B cells. We therefore further investigated the involvement of two ubiquitously expressed intracellular cAMP effectors, PKA and an exchange protein directly activated by cAMP (Epac). A specific PKA inhibitor (PKI) significantly inhibited the synergistic induction of PDE4B2 by NTHi and roflumilast. The inhibitor polypeptide TTYADFIASGRTGRRNAIHD (SEQ ID NO: 3) can be readily synthesized and is also available from Santa Cruz Biotechnologies. PKI and active fragments or variants thereof (eg, polypeptides at least 80% (eg, 85%, 90%, or 95%) identical t...

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Abstract

The invention discloses compositions and methods for treating COPD and other inflammatory conditions. The present invention features, inter alia, pharmaceutical compositions and their use in the preparation of a medicament (e.g., a medicament for inflammation, such as an inflammatory lung disease) or in a therapeutic regimen. The compositions can include at least two active agents: a first agent that inhibits PDE4 (e.g., roflumilast) and a second active agent that inhibits the expression or activity of one or more PDE4B variants (e.g., PDE4B2). The compositions and methods will attenuate an unwanted up-regulation of a PDE4B (e.g., PDE4B2) and may thereby improve treatment with the first agent (e.g., roflumilast). For example, the second agent may improve the efficacy of the first agent, decrease the effective dose of the first agent, ameliorate the tolerance to the first agent that would otherwise develop (e.g., in patients with COPD exacerbation), reduce unwanted side effects caused by the first agent, or otherwise improve treatment regimes including a PDE4 inhibitor.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the priority date of U.S. Provisional Application 62 / 136,115, filed March 20, 2015. The entire content of this prior application is hereby incorporated by reference. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with government support under grant number DC005843 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The present invention relates to compositions and methods for the combined use of at least two active agents that inhibit phosphodiesterases in a family defined as Family 4 (PDE4), and more particularly to compounds comprising such as Combination therapy of roflumilast and a second agent that inhibits PDE4 of the B subfamily (ie, PDE4B such as PDE4B2). The compositions and methods will attenuate undesired upregulation of PDE4B, such as PDE4B2, thereby allow...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61K31/085A61K31/165C12N5/10A61P11/00
CPCA61K45/06A61K31/423A61P11/00A61K31/44A61K31/12A61K31/573C12N9/16C12Y301/04053A61K2300/00A61K9/0053A61K9/0073A61K9/7023A61K31/7088A61K35/74
Inventor 李建东
Owner GEORGIA STATE UNIV RES FOUND INC
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