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Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil

Richard W. Chapman, Michel R. Corboz, Carlos Fernandez, Eugene Sullivan, Andy Stautberg, Adam J. Plaunt, Donna M. Konicek, Vladimir Malinin, Zhili Li, David Cipolla, Walter Perkins
ERJ Open Research 2021 7: 00592-2020; DOI: 10.1183/23120541.00592-2020
Richard W. Chapman
Insmed Incorporated, Bridgewater, NJ, USA
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  • For correspondence: richard.chapman@insmed.com
Michel R. Corboz
Insmed Incorporated, Bridgewater, NJ, USA
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Carlos Fernandez
Insmed Incorporated, Bridgewater, NJ, USA
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Eugene Sullivan
Insmed Incorporated, Bridgewater, NJ, USA
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Andy Stautberg
Insmed Incorporated, Bridgewater, NJ, USA
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Adam J. Plaunt
Insmed Incorporated, Bridgewater, NJ, USA
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Donna M. Konicek
Insmed Incorporated, Bridgewater, NJ, USA
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Vladimir Malinin
Insmed Incorporated, Bridgewater, NJ, USA
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Zhili Li
Insmed Incorporated, Bridgewater, NJ, USA
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David Cipolla
Insmed Incorporated, Bridgewater, NJ, USA
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Walter Perkins
Insmed Incorporated, Bridgewater, NJ, USA
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  • FIGURE 1
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    FIGURE 1

    Cough induced by increasing doses of treprostinil (TRE) and dry powder formulation of treprostinil palmitil (TPIP) in guinea pigs. Values are the mean±sem cough counts following exposure to a) TRE (n=4–10), b) TPIP (n=4–6) and c) the time to the first cough for both TRE and TPIP. *: p<0.05 compared to vehicle.

  • FIGURE 2
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    FIGURE 2

    Plethysmograms of one guinea pig showing changes in inspiratory (Insp) and expiratory (Exp) airflows following exposure to treprostinil (TRE). a) Seven cough “bouts” evoked by a 10-min exposure to TRE (3.30 μg·kg−1). b) Expanded view of one of the cough bouts with 22 individual coughs enumerated.

  • FIGURE 3
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    FIGURE 3

    Effect of dry powder formulation of treprostinil palmitil (TPIP) and mannitol vehicle on ventilation and Penh in guinea pigs. Data are shown at baseline (time=0 min), during exposure to TPIP (time=0–15 min) and following TPIP exposure (time=15–135 min). TPIP was administered at an inhaled dose of 35.8 μg·kg−1. a) respiratory rate (f), b) tidal volume (VT), c) minute ventilation (V′E), and d) Penh (enhanced pause) over time. Values are the mean±sem (n=6 for TPIS and n=4 for mannitol vehicle).

  • FIGURE 4
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    FIGURE 4

    Effects of prostanoid receptor antagonists, a tachykinin NK1 receptor antagonist, a bradykinin B2 receptor antagonist and a cyclooxygenase inhibitor on treprostinil (TRE) cough in guinea pigs. The compound (blue bars) or their respective vehicles (white bars) were administered intraperitoneally (30 min) or by aerosol (10 min) prior to nebulised TRE (3.30 μg·kg−1). Graphs show the mean±sem effects against TRE-induced cough of a) the IP receptor antagonist (RO 1138452, 10 mg·kg−1 i.p., n=5), the EP1 receptor antagonist (ONO-8711, 10 mg·kg−1 i.p., n=5–6), the EP2 receptor antagonist (PF-04418948, 5 mg·kg−1 i.p., n=5), the EP3 receptor antagonist (L-798106, 10 mg·kg−1 i.p., n=5–7) and the DP1 receptor antagonist (BW A868C 10 mg·kg−1 i.p., n=5); and b) the NK1 receptor antagonist (CP99994, 10 mg·kg−1, i.p., n=5), the bradykinin B2 receptor antagonist (HOE 140, 1 mg·mL−1 delivered by aerosol, n=3) and the cyclooxygenase (COX) inhibitor (meclofenamic acid, 1 mg·kg−1 i.p., n=3). *: p<0.05 compared to vehicle.

  • FIGURE 5
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    FIGURE 5

    Nebulisation of treprostinil (TRE) to the isolated laryngeal airway of rats produced no reflex effects, whereas nebulised citric acid produced concentration-dependent a) apnoea and b) increased the frequency of swallows. The apnoeic ratio was calculated as the TE treatment/TE baseline, where TE represents the duration of expiration. Values are the mean±sem (n=5 for saline, n=5 for citric acid, n=6 for TRE at 0.1 mM and n=2 for TRE at 0.3 to 1.5 mM). *: p<0.05 compared to saline.

  • FIGURE 6
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    FIGURE 6

    Intravenous treprostinil (TRE) produced no reflex effects, whereas intravenous capsaicin produced a) apnoea and b) a decrease in mean arterial blood pressure (MAP). The apnoeic ratio was calculated as described in the legend to figure 5. Values represent the mean±sem (n=3). *: p<0.05 compared to saline.

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Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil
Richard W. Chapman, Michel R. Corboz, Carlos Fernandez, Eugene Sullivan, Andy Stautberg, Adam J. Plaunt, Donna M. Konicek, Vladimir Malinin, Zhili Li, David Cipolla, Walter Perkins
ERJ Open Research Jan 2021, 7 (1) 00592-2020; DOI: 10.1183/23120541.00592-2020

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Characterisation of cough evoked by inhaled treprostinil and treprostinil palmitil
Richard W. Chapman, Michel R. Corboz, Carlos Fernandez, Eugene Sullivan, Andy Stautberg, Adam J. Plaunt, Donna M. Konicek, Vladimir Malinin, Zhili Li, David Cipolla, Walter Perkins
ERJ Open Research Jan 2021, 7 (1) 00592-2020; DOI: 10.1183/23120541.00592-2020
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