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P.3.d.021 EGIS-11148: pharmacological characterization of a new atypical antipsychotic compound
S460
P.3.d Psychotic disorders and antipsychotics – Antipsychotics (basic)
stimulus was a tone modulated in amplitude by a sinusoid with linerly-increasing frequency from 1 to 250 Hz. 12 healthy controls and 15 patients with schizophrenia participiated in the study. Eight patients were under atypical neuroleptic treatment (risperidone (n = 2), olanzapine (n= 3), quetiapine and risperidone (n = 1), aripiprazol (n = 1), clozapine (n = 1) and 7 patients were receiving no treatment. Results: The pattern observed in the chirp-evoked potential was very similar in all healthy subjects. However, we found a high variability in the frequency of maximal response, below the normal values in 6 of the 7 treated patients. A maximal response in the lower limit of normality was seen only in one untreated patient. Maximal frequence was significantly lower in schizophrenia patients than in controls (p < 0.05). Conclusions: In conclusion, our findings suggest that atypical neuroleptics may modify cortical oscillatory activity in terms of frequency. We propose the use of simultaneus measure of the response to multiple, rather than fixed frequencies as a method for further studies of cortical oscillatory activity and the relation between neuroleptic treatment and clinical and cognitive improvement. Table 1. Pt Treatment
Amplitude Frequency Comments max. max.
1
Risperidone 6 mg/day
0.11
47
2
0.78
34
3
Risperidone depot. 50 mg/2 weeks Olanzapine 20 mg/day
0.86
39
4
Olanzapine 12.5 mg/day 0.56
45
5
Olanzapine 5 mg/day
0.65
34
6
7.57
38
7
Quetiapine 200 mg/day Risperidone Aripiprazol 15 mg/day
2.1
48
8
Clozapine 400 mg/day
0.82
41
9
None
0.22
55
10 None
0.52
46
11 None
0.39
47
12 None
0.21
32
13 None
0.31
43
14 None
0.44
44
15 None
0.18
35
Very low amplitude Normal frequence Normal amplitude Low frequence Normal amplitude Low frequence Normal amplitude Low frequence Normal amplitude Low frequence Very high amplitude Low frequence Very high amplitude Normal frequence Normal amplitude Low frequence Low amplitude Normal frequence Low amplitude Normal frequence Low amplitude Normal frequence Low amplitude Low frequence Low amplitude Low frequence Low amplitude Normal frequence Low amplitude Low frequence
References [1] Artieda J, Valencia M, Alegre M, et al., 2004, Potentials evoked by chirp-modulated tones: a new technique to evaluate oscillatory activity in the auditory pathway. Clin Neurophysiol 115(3), 699–709. [2] Light G, Hsu J, Hsieh M, Meyer-Gomes K, Sprock J, Swerdlow N, Braff D, 2006, Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients. Biol Psychiatry 60(11), 1231–1240.
P.3.d.021 EGIS-11148: pharmacological characterization of a new atypical antipsychotic compound G. Levay1 ° , K. Moricz1 , H. Kompagne1 , S. Kertesz1 , J. Barkoczy1 , L. Harsing1 , I. Gacsalyi1 . 1 Egis Pharmaceuticals ltd, Division of Preclinical Research, Budapest, Hungary Introduction: The pyridazinone derivative EGIS-11148 has been synthesized at EGIS Pharmaceuticals Plc as a potential antipsychotic compound. Recently, another antipsychotic drug candidate EGIS-11150/S36549 has been intraduced into phase I clinical development. Pyridazinone antipsychotic compounds show special charcteristics to antagonise the effects of phencyclidine (PCP). PCP acts on the central nervous system as a propsychotic agent, both in animals and man. PCP treated animals show typical alterations in EEG power especially in the theta frequency band thougt to reflect the propsychotic properties of the compound. The pyridazinone compounds, and among them EGIS-11150/S36549 normalises EEG power spectra in as low as 0.01 mg/kg concentration. Similarly, EGIS-11150/S36549 normalises PCP-induced behavioral changes in rats by reducing stereotype activities and social withdrawal. The purpose of this study was to pharmacologically characterise a potential backup compound to EGIS11150/S36549 and to investigate if similar impact on PCP-induced changes are characteristic to the compound. Methods: In vitro receptor assay on 5-HT1A, 1D, 2A, 2C, 6, 7, 5-HT uptake, dopaminergic D1, D2, D4, noradrenergic, alpha1, alpha2, beta, muscarinic, sigma, GABA a, GABA b 1,4 benzodiazepine receptors, inhibition of phencyclidine-induced hypermotility, inhibition of DOI-induced hyperthermia, prepulse inhibition of acoustic startle, disrupted by phencyclidine, inhibition of apomorphine induced climbing and stereotype, inhibition of conditioned avoidance response and examination of cataleptogenic effect were used. Summary of results: In receptor assays EGIS-11148 has been found to have high affinity at 5-HT2A serotonergic and alpha1 adrenoceptors (Ki: 37 nM and 1.3 nM respectively), and mediumlow affinity at dopaminergic D2 receptors (Ki: 170 nM) Weak binding to other receptors such as 5-HT6, 5-HT7, and alpha2 receptors might also influence efficacy of this compound in experimental models. Due to the multireceptorial binding properties resembling that of clozapine, the compound has been tested for antipsychotic-like efficacy and was found to exert significant activity in several animal models. EGIS-11148 inhibited phencyclidine (PCP) induced hypermotility in mice as well as DOI induced hyperthermia in rats in significantly lower dose than that of clozapine. Prepulse inhibition (PPI) of acoustic startle disrupted by phencyclidine was normalized by EGIS-11148 in rats. Beside atypical antipsychotic-like properties the compound displayed efficacy in classical models such as inhibition of apomorphine induced climbing and stereotypies. (per os ID50: 0.6 mg/kg and 2.0 mg/kg, respectively) The compound exerted 50% inhibition of the conditioned avoidance response (CAR) in 3.0 mg/kg dose while clozapine displayed the same extent of inhibition in approx. seven times higher dose (21.2 mg/kg). Induction of extrapyramidal side effect has been evaluated by measurement of cataleptogenic effect of the compound. First signs of catalepsy have been seen at 10 mg/kg, approximately three times higher dose than that produced antipsychotic-like effects in rats. These results show that EGIS-11148, similarly to EGIS-11150/S36549, is a valuable member of the antipsychotic pyridazinone compounds with innovative pharmacology.
P.3.d Psychotic disorders and antipsychotics – Antipsychotics (basic)
stimulus was a tone modulated in amplitude by a sinusoid with linerly-increasing frequency from 1 to 250 Hz. 12 healthy controls and 15 patients with schizophrenia participiated in the study. Eight patients were under atypical neuroleptic treatment (risperidone (n = 2), olanzapine (n= 3), quetiapine and risperidone (n = 1), aripiprazol (n = 1), clozapine (n = 1) and 7 patients were receiving no treatment. Results: The pattern observed in the chirp-evoked potential was very similar in all healthy subjects. However, we found a high variability in the frequency of maximal response, below the normal values in 6 of the 7 treated patients. A maximal response in the lower limit of normality was seen only in one untreated patient. Maximal frequence was significantly lower in schizophrenia patients than in controls (p < 0.05). Conclusions: In conclusion, our findings suggest that atypical neuroleptics may modify cortical oscillatory activity in terms of frequency. We propose the use of simultaneus measure of the response to multiple, rather than fixed frequencies as a method for further studies of cortical oscillatory activity and the relation between neuroleptic treatment and clinical and cognitive improvement. Table 1. Pt Treatment
Amplitude Frequency Comments max. max.
1
Risperidone 6 mg/day
0.11
47
2
0.78
34
3
Risperidone depot. 50 mg/2 weeks Olanzapine 20 mg/day
0.86
39
4
Olanzapine 12.5 mg/day 0.56
45
5
Olanzapine 5 mg/day
0.65
34
6
7.57
38
7
Quetiapine 200 mg/day Risperidone Aripiprazol 15 mg/day
2.1
48
8
Clozapine 400 mg/day
0.82
41
9
None
0.22
55
10 None
0.52
46
11 None
0.39
47
12 None
0.21
32
13 None
0.31
43
14 None
0.44
44
15 None
0.18
35
Very low amplitude Normal frequence Normal amplitude Low frequence Normal amplitude Low frequence Normal amplitude Low frequence Normal amplitude Low frequence Very high amplitude Low frequence Very high amplitude Normal frequence Normal amplitude Low frequence Low amplitude Normal frequence Low amplitude Normal frequence Low amplitude Normal frequence Low amplitude Low frequence Low amplitude Low frequence Low amplitude Normal frequence Low amplitude Low frequence
References [1] Artieda J, Valencia M, Alegre M, et al., 2004, Potentials evoked by chirp-modulated tones: a new technique to evaluate oscillatory activity in the auditory pathway. Clin Neurophysiol 115(3), 699–709. [2] Light G, Hsu J, Hsieh M, Meyer-Gomes K, Sprock J, Swerdlow N, Braff D, 2006, Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients. Biol Psychiatry 60(11), 1231–1240.
P.3.d.021 EGIS-11148: pharmacological characterization of a new atypical antipsychotic compound G. Levay1 ° , K. Moricz1 , H. Kompagne1 , S. Kertesz1 , J. Barkoczy1 , L. Harsing1 , I. Gacsalyi1 . 1 Egis Pharmaceuticals ltd, Division of Preclinical Research, Budapest, Hungary Introduction: The pyridazinone derivative EGIS-11148 has been synthesized at EGIS Pharmaceuticals Plc as a potential antipsychotic compound. Recently, another antipsychotic drug candidate EGIS-11150/S36549 has been intraduced into phase I clinical development. Pyridazinone antipsychotic compounds show special charcteristics to antagonise the effects of phencyclidine (PCP). PCP acts on the central nervous system as a propsychotic agent, both in animals and man. PCP treated animals show typical alterations in EEG power especially in the theta frequency band thougt to reflect the propsychotic properties of the compound. The pyridazinone compounds, and among them EGIS-11150/S36549 normalises EEG power spectra in as low as 0.01 mg/kg concentration. Similarly, EGIS-11150/S36549 normalises PCP-induced behavioral changes in rats by reducing stereotype activities and social withdrawal. The purpose of this study was to pharmacologically characterise a potential backup compound to EGIS11150/S36549 and to investigate if similar impact on PCP-induced changes are characteristic to the compound. Methods: In vitro receptor assay on 5-HT1A, 1D, 2A, 2C, 6, 7, 5-HT uptake, dopaminergic D1, D2, D4, noradrenergic, alpha1, alpha2, beta, muscarinic, sigma, GABA a, GABA b 1,4 benzodiazepine receptors, inhibition of phencyclidine-induced hypermotility, inhibition of DOI-induced hyperthermia, prepulse inhibition of acoustic startle, disrupted by phencyclidine, inhibition of apomorphine induced climbing and stereotype, inhibition of conditioned avoidance response and examination of cataleptogenic effect were used. Summary of results: In receptor assays EGIS-11148 has been found to have high affinity at 5-HT2A serotonergic and alpha1 adrenoceptors (Ki: 37 nM and 1.3 nM respectively), and mediumlow affinity at dopaminergic D2 receptors (Ki: 170 nM) Weak binding to other receptors such as 5-HT6, 5-HT7, and alpha2 receptors might also influence efficacy of this compound in experimental models. Due to the multireceptorial binding properties resembling that of clozapine, the compound has been tested for antipsychotic-like efficacy and was found to exert significant activity in several animal models. EGIS-11148 inhibited phencyclidine (PCP) induced hypermotility in mice as well as DOI induced hyperthermia in rats in significantly lower dose than that of clozapine. Prepulse inhibition (PPI) of acoustic startle disrupted by phencyclidine was normalized by EGIS-11148 in rats. Beside atypical antipsychotic-like properties the compound displayed efficacy in classical models such as inhibition of apomorphine induced climbing and stereotypies. (per os ID50: 0.6 mg/kg and 2.0 mg/kg, respectively) The compound exerted 50% inhibition of the conditioned avoidance response (CAR) in 3.0 mg/kg dose while clozapine displayed the same extent of inhibition in approx. seven times higher dose (21.2 mg/kg). Induction of extrapyramidal side effect has been evaluated by measurement of cataleptogenic effect of the compound. First signs of catalepsy have been seen at 10 mg/kg, approximately three times higher dose than that produced antipsychotic-like effects in rats. These results show that EGIS-11148, similarly to EGIS-11150/S36549, is a valuable member of the antipsychotic pyridazinone compounds with innovative pharmacology.