Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews

Article

Author: Hui, Jessica C M ; Du, Peng ; Khalid, Aleena ; Cui, Dexuan ; Deng, Yingyi ; Liu, Luping ; Jiang, Bin ; Liu, Julia Y H ; Ngan, M P ; Yang, Lingqing ; Chan, S W ; Lu, Zengbing ; Ng, Heidi S H ; Rudd, John A

BACKGROUND AND AIMSThe contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus.METHODSThe effects of substance P (SP), neurokinin (NK)A, NKB and selective NK₁ (CP122,721, CP99,994), NK₂ (SR48,968, GR159,897) and NK₃ (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array.RESULTSCompared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK₃ had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon.CONCLUSIONThis study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.

01 Oct 2013·NeuropharmacologyQ2 · MEDICINE

NK1 receptor antagonism lowers occupancy requirement for antidepressant-like effects of SSRIs in the Gerbil forced swim test

Q2 · MEDICINE

Article

Author: Snjezana Lelas ; Nicholas J. Lodge ; John E. Macor ; Kevin W. Gillman ; Matthew T. Taber ; Michael F. Parker ; Joanne J. Bronson ; Yu-Wen Li ; Tanya L. Wallace-Boone ; Carl D. Davis ; Rick L. Pieschl ; Thaddeus F. Molski ; Amy E. Newton ; Kimberly S. Newberry

The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.

01 Sep 2013·Expert Opinion on Drug SafetyQ3 · MEDICINE

Safety of neurokinin-1 receptor antagonists

Q3 · MEDICINE

Review

Author: Rafael Coveñas ; Miguel Muñoz

INTRODUCTIONThe substance P (SP)/neurokinin (NK)-1 receptor system is involved in many pathological processes. NK-1 receptor antagonists have many promising therapeutic indications. However, the only NK-1 receptor antagonist used in clinical practice is the drug aprepitant and its intravenously administered prodrug, fosaprepitant. In general, NK-1 receptor antagonists are safe and well tolerated.AREAS COVEREDA search was carried out in Medline using the following terms: adverse events, aprepitant, casopitant, clinical trials, CP-122,721, ezlopitant, fosaprepitant, NK-1 receptor antagonists, randomized, safety, side effects, tolerability and vofopitant.EXPERT OPINIONMost clinical trials have focused on the antiemetic action of aprepitant in cancer patients treated with chemotherapy. However, the efficacy and safety of aprepitant have not been fully tested in other diseases in which the SP/NK-1 receptor system is involved (e.g., cancer, HIV, alcoholism); thus, clinical trials are required. The use of NK-1 receptor antagonists in oncology therapy is quite promising, but to date pharmacological therapy has not exploited the many possible therapies offered by such antagonists.

100 Deals associated with CP-122721

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Phase 2	-	Pfizer Inc.	-
Depressive Disorder, Major	Phase 2	US	Pfizer Inc.	-
Nausea and vomiting	Phase 2	US	Pfizer Inc.	-
Pain	Phase 2	US	Pfizer Inc.	-

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