Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

Michelson, David; Hargreaves, Richard; Alexander, Robert; Ceesay, Paulette; Hietala, Jarmo; Reines, Scott A.

doi:10.1017/s1461145712000065

Cited by 38 publications

(22 citation statements)

References 28 publications

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“…Total RNA extraction and DNAse treatment were performed as previously described (Alboni et al, 2013): 1 µg of total RNA was reverse transcribed with High Capacity cDNA Reverse Transcription Kit (Life Technologies Corporation, Carlsbad, CA, USA) in 20 µL of reaction mix.…”

Section: Methodsmentioning

confidence: 99%

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

Alboni

Montanari

Benatti

et al. 2014

Brain, Behavior, and Immunity

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Interleukin (IL)- 18 is a cytokine previously demonstrated to participate in neuroinflammatory processes. Since the components of the IL-18 receptor complex are expressed in neurons throughout the brain, IL-18 is also believed to directly influence neuronal function. Here we tested this hypothesis on mouse hippocampal neurons by measuring the effects of IL-18 on three pathways previously shown to be regulated by this cytokine in non-neuronal cells: the MAPK pathways, p38 and ERK1/2 MAPKs, STAT3 and NF-κB. Experiments were carried out in vitro using the immortalized hippocampal neuronal line HT-22 or in vivo following i.c.v. injection with recombinant mouse IL-18. We showed that IL-18 did not activate NF-κB in HT-22 cells whereas it induced a rapid (within 15 minutes) activation of the MAPK pathways. Moreover, we demonstrated that IL-18 treatment enhanced P-STAT3 (Tyr705)/ STAT3 ratio in the nucleus of HT-22 cells after 30–60 minutes of exposure. A similar increase in P-STAT3 (Tyr705)/ STAT3 ratio was observed in the whole hippocampus one hour after i.c.v. injection. These data demonstrate that IL-18 can act directly on neuronal cells affecting the STAT3 pathway; therefore, possibly regulating the expression of specific genes within the hippocampus. This effect may help to explain some of the IL-18- induced effects on synaptic plasticity and functionality within the hippocampal system.

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Section: Methodsmentioning

confidence: 99%

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

Alboni

Montanari

Benatti

et al. 2014

Brain, Behavior, and Immunity

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“…No systematic pattern of laboratory abnormalities was observed [80]. A lack of efficacy of L-759,274 for the treatment of generalized anxiety disorder has been reported [81].…”

Section: L-759274mentioning

confidence: 98%

Safety of neurokinin-1 receptor antagonists

Muñoz

Coveñas

2013

Expert Opinion on Drug Safety

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Most 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.

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“…Purdon et al [19] also reported results for the Beck Depression Inventory (BDI) and found no significant difference. Moreover, a recent meta-analysis examined the efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis and found that quetiapine was similar to haloperidol regarding depression [22]. …”

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of quetiapine versus haloperidol in first-episode schizophrenia: a randomized clinical trial

Amr¹,

Lakhan²,

Sanhan³

et al. 2013

Int Arch Med

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BackgroundSchizophrenia is a chronic disease of global importance. The second-generation antipsychotic quetiapine has a favorable side-effect profile, however, its clinical effectiveness has been called into question when compared with first-generation antipsychotics such as haloperidol. This study evaluates the efficacy and tolerability of quetiapine versus haloperidol for first-episode schizophrenia in the outpatient setting.Methods156 adult patients with first-episode schizophrenia participated in an outpatient clinical trial and were randomized to quetiapine (200 mg/d; n = 78) or haloperidol (5 mg/d; n = 78). The study medications were titrated to a mean daily dose of 705 mg for quetiapeine and 14 mg for haloperidol. The patients were assessed at baseline, six weeks, and twelve weeks. The primary outcome measures were positive and negative scores of the Positive and Negative Syndrome Scale (PANSS). Secondary measures were Global Assessment of Functioning (GAF) scale for overall psychosocial functioning, and Simpson-Angus Scale (SAS) for extra-pyramidal symptoms.ResultsAt twelve weeks, the quetiapine group had a greater decrease in PANSS positive (18.9 vs. 15.3, p = 0.013) and negative scores (15.5 vs. 11.6, p = 0.012), however, haloperidol showed a greater decrease in general psychopathology score (23.8 vs. 27.7, p = 0.012). No significant difference between groups were found for total PANSS (58.3 vs. 54.8, p = 0.24) and GAF (45.7 vs. 46.2, p = 0.79).ANOVA identified significant group interactions on PANSS positive (F = 18.72, df = 1.6,52.4, p < 0.0001), negative (F = 5.20, df = 1.1,35.7, p < 0.0001), depression/anxiety (F = 106.49, df = 1.14,37.8, p < 0.0001), and total scores (F = 7.51, df = 1.4,45.6, p = 0.001).SAS (8.62 vs. 0.26, p < 0.0001) and adverse events of akathisia (78% vs. 0%, p = 0.000), parkinsonism (66.6% vs. 0%, p < 0.0001), and fatigue (84.6% vs. 66.6%, p = 0.009) were greater in haloperidol compared to quetiapine, whereas headache was more common in quetiapine treated patients (11.5% vs. 35.9%, p < 0.0001).ConclusionsQuetiapine has greater efficacy for positive and negative symptoms with less extra-pyramidal symptoms than haloperidol when used for first-episode schizophrenia in the outpatient setting.

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Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

Cited by 38 publications

References 28 publications

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells

Safety of neurokinin-1 receptor antagonists

Efficacy and tolerability of quetiapine versus haloperidol in first-episode schizophrenia: a randomized clinical trial

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