Philippe Nuss

Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes

Animal studies indicate that the anxiolytic properties of the antipsychotic agent cyamemazine may result from blockade of serotonin 5-HT(2C) receptors and to a lesser extent from blockade of serotonin 5-HT(3) receptors. Here, we used human recombinant receptors to determine the relative affinity of cyamemazine for serotonin and dopamine receptor subtypes. In addition, cyamemazine was tested in other brain receptor types and subtypes which are considered to mediate central nervous systems effects of drugs. Hence, cyamemazine affinity was determined in human recombinant receptors expressed in CHO cells (hD(2), hD(3), and hD(4.4) receptors, h5-HT(1A), h5-HT(2A), h5-HT(2C), and h5-HT(7), and hM(1), hM(2), hM(3), hM(4), and hM(5) receptors), L-cells (hD(1) receptor), and HEK-293 cells (h5-HT(3) receptors) or natively present in N1E-115 cells (5-HT(3) receptors) or in rat cerebral cortex (non-specific alpha(1)- and alpha(2)-adrenoceptors, GABA(A) and GABA(B) receptors, H(3) histamine receptors), and guinea-pig cerebellum (H(1) central and H(2) histamine receptors) membranes. Similarly to atypical antipsychotics, cyamemazine exhibited high affinity for: (i) h5-HT(2A) receptors (K(i)=1.5+/-0.7 nM, mean+/-SEM, N=3) and this was four times higher than for hD(2) receptors (K(i)=5.8+/-0.8 nM), (ii) h5-HT(2C) receptors (K(i)=11.8+/-2.2nM), and (iii) 5-HT(7) receptors (K(i)=22 nM). Conversely, cyamemazine exhibited very low affinity for h5-HT(3) receptors (K(i)=2.9+/-0.4 microM). In conclusion, similarly to atypical antipsychotic agents, cyamemazine, possesses high affinity for h5-HT(2A), h5-HT(2C), and h5-HT(7) receptors, a feature which can explain its low propensity to cause extrapyramidal adverse reactions in clinical practice. The high affinity for h5-HT(2C) receptors, but not for h5-HT(3) receptors, can account for the anxiolytic activity of cyamemazine in human subjects.

Revisiting loxapine: a systematic review

Loxapine is an antipsychotic used in psychiatry for over 40 years with a well-established profile. Loxapine is a dibenzoxazepine tricyclic antipsychotic agent, available for oral, intramuscular and inhalatory administration. In the light of the recent approval by the regulatory agencies of inhaled loxapine for use in the acute treatment of mild-to-moderate agitation in adults affected with schizophrenia or bipolar disorder, this article aims to critically review the available literature on loxapine, irrespective of its formulation.This review examines the efficacy and tolerability of the various formulations of loxapine in the treatment of agitation and aggression in patients affected with schizophrenia, bipolar disorder and other psychiatric conditions.A comprehensive and systematic literature search of PubMed/MEDLINE was conducted, and relevant pharmacodynamic and pharmacokinetic data was included. The findings from the literature were critically reviewed and synthesized.The available data suggests that the antipsychotic efficacy of loxapine is similar to the efficacy of other typical or atypical antipsychotics, with an adverse effects profile comparable to that of the typical antipsychotics at high doses for chronic treatment. As an acute treatment in agitation associated with schizophrenia or bipolar disorder, inhaled loxapine was developed as an innovative and rapid option which appears to be efficacious and tolerable.

Antipsychotic medication, functional outcome and quality of life in schizophrenia: focus on amisulpride

Abstract Background: Restoration of quality of life is considered as the ultimate treatment goal in the management of schizophrenia and is important for destigmatising the disease. However, few studies, including the most recent, have collected quality of life data prospectively or evaluated the relationship of treatment with quality of life. Scope: Amisulpride is an atypical antipsychotic drug which has been described to have potency in improving negative symptoms of chronic schizophrenia and whose use is associated with a relatively low rate of emergence of extrapyramidal side-effects. These properties may contribute to a beneficial effect on quality of life. A systematic literature review of functional outcome in clinical trials with amisulpride was performed in order to assess the effect of this drug on quality of life and social functioning in patients. The Medline database was searched for all studies of amisulpride in schizophrenia which reported functional and quality of life outcomes up until 30 September 2009. Findings: Only one dedicated study assessing functional outcome or quality of life as a primary outcome criterion was identified. This demonstrated significant improvement in subjective well-being in patients with schizophrenia initiating treatment with amisulpride, and a correlation between this improvement and amelioration of psychopathology. In addition, functional outcome rating scales were used as secondary outcome measures in eight randomised clinical trials, and two naturalistic observational studies. Amisulpride treatment was associated with improvement in functional outcome, with effect sizes that were comparable between studies. Improvements in functional outcome are consistently greater than those observed in patients treated with haloperidol and similar in magnitude to those seen with three other atypical antipsychotics, namely olanzapine, ziprasidone and risperidone. A patient-reported outcome measure was used in only one comparative study, and demonstrated perception of a superior benefit with amisulpride compared to haloperidol. These findings could to some extent be replicated in several large naturalistic studies under standard conditions of care. Conclusions: The data from studies on functional outcome and subjective well-being provide consistent information supporting the use of amisulpride for the treatment of schizophrenia in order to improve social functioning, integration into the community and autonomy, which are critical for the overall quality of life of patients with schizophrenia.

Phospholipase A2-Induced Remodeling Processes on Liquid-Ordered/Liquid-Disordered Membranes Containing Docosahexaenoic or Oleic Acid: A Comparison Study.

Vesicle cycling, which is an important biological event, involves the interplay between membrane lipids and proteins, among which the enzyme phospholipase A2 (PLA2) plays a critical role. The capacity of PLA2 to trigger the budding and fission of liquid-ordered (L(o)) domains has been examined in palmitoyl-docosahexaenoylphosphatidylcholine (PDPC) and palmitoyl-oleoylphosphatidylcholine (POPC)/sphingomyelin/cholesterol membranes. They both exhibited a L(o)/liquid-disordered (L(d)) phase separation. We demonstrated that PLA2 was able to trigger budding in PDPC-containing vesicles but not POPC ones. The enzymatic activity, line tension, and elasticity of the membrane surrounding the L(o) domains are critical for budding. The higher line tension of Lo domains in PDPC mixtures was assigned to the greater difference in order parameters of the coexisting phases. The higher amount of lysophosphatidylcholine generated by PLA2 in the PDPC-containing mixtures led to a less-rigid membrane, compared to POPC. The more elastic L(d) membranes in PDPC mixtures exert a lower counteracting force against the L(o) domain bending.