panamesine and Schizophrenia

Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antipsychotic Agents; Blood Cell Count; Double-Blind Method; Electroencephalography; Female; Humans; Locus Coeruleus; Male; Oxazoles; Piperidines; Receptors, sigma; Schizophrenia; Sleep; Tumor Necrosis Factor-alpha

EMD 57455 (panamesine) is a new sigma receptor ligand alleged to have antipsychotic effects. Animal studies have demonstrated that EMD 57445 has a functional antidopaminergic activity without extrapyramidal side effects and a c-fos expression pattern similar to that obtained with atypical neuroleptics. Therefore, the substance might be of interest for the treatment of schizophrenia. The present article describes the results of an exploratory open clinical trial that was aimed at determining the appropriate dose range for clinical efficacy and safety of EMD 57455 in patients with an acute episode of schizophrenia. In a treatment period of 4 weeks, 12 patients received EMD 57445 up to 60 mg/day for 4 weeks. Seven patients completed the study: four were classified as responders (as defined by at least a 50% decrease in the BPRS total score), two improved slightly and one patient remained unimproved. The intent-to-treat analysis showed significant improvement in the psychometric variables assessed by the Brief Psychiatric Rating Scale, Clinical Global Impression and Positive and Negative Symptoms Scale. Major side effects were extrapyramidal symptoms in two patients and restlessness in one patient. With respect to efficacy and safety, our data agree with a previous study, except that in our study EMD 57455 was not totally free of extrapyramidal side effects.

Topics: Adult; Antipsychotic Agents; Female; Humans; Ligands; Male; Middle Aged; Oxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, sigma; Schizophrenia; Schizophrenic Psychology

Antipsychotic efficacy and side effects of the selective sigma ligand EMD 57445 (panamesine) were investigated in 12 patients (6 males, 6 females) who met DSM-III-R criteria for schizophrenia. A 4-week open clinical study revealed only modest effects of EMD 57445 and its metabolites on positive and negative symptoms of schizophrenia. Extrapyramidal and other side effects were moderate, although a significant increase in mild dyskinetic movements was found. Five patients, four of whom were females, completed the trial. Dropouts were mainly due to treatment failure. Antipsychotic effects were significantly greater in female than male patients.

Topics: Acute Disease; Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Biotransformation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Oxazoles; Piperidines; Psychiatric Status Rating Scales; Receptors, sigma; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The sigma (sigma) receptor has been proposed as a target of neuroleptic drugs. Preclinical data suggest that panamesine (EMD 57445), a novel sigma ligand, has antipsychotic effects and is free of side effects related to the extrapyramidal motoric system (EPMS). Here we report the results of an exploratory study aimed at determining the appropriate dose range and the safety of panamesine in patients with an acute episode of schizophrenia. The first trial with four patients revealed insufficient clinical efficacy of a protocol where the daily dosage was increased stepwise from 7.5 mg during week 1, up to 30 mg during weeks 3 and 4. In a second set of trials, 12 patients received 15 mg at the beginning, this being increased up to 60 mg/day within 3 days and then maintained at this level for 4 weeks. As assessed by a decrease in the Brief Psychiatric Rating Scale score by at least 50%, five patients were judged as responders, whereas six patients showed only a slight improvement, and one deteriorated. Moreover, intent-to-treat analysis showed significant improvement in psychometric variables. In all patients prolactin levels increased during treatment, probably due to an active metabolite with weak dopamine-2-receptor antagonistic effects. No major side effects occurred, and in particular, no EPMS symptoms were seen.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Female; Humans; Male; Oxazoles; Piperidines; Prolactin; Receptors, sigma; Schizophrenia; Sleep

EMD 57445 (panamesine) is a high affinity sigma ligand with the profile of an atypical antipsychotic in animal studies. It has been reported recently to have antipsychotic activity in schizophrenia. However, its metabolite, EMD 59983, binds also to D(2) and D(3) dopamine (DA) receptors.. The aim of this study was to test, using single photon emission computed tomography (SPECT) and [(123)I]iodobenzamide (IBZM) as the radiotracer, whether EMD 59983 would pass the blood-brain barrier and to what extent it would contribute to the effects of EMD 57445 in schizophrenia.. Two IBZM SPECT-scans were performed in five neuroleptic-free schizophrenic patients (DSM IV), one before and one after treatment with 60 mg panamesine daily for a treatment duration of 12-26 days.. A high occupancy of striatal D(2)-like DA receptors similar to that induced by typical neuroleptics was observed in all patients treated with EMD 57445.. Our results suggest that a possible antipsychotic activity of EMD 57445 in schizophrenia is not necessarily attributable to its affinity for sigma receptors, but could be simply due to the potent antidopaminergic effects of EMD 59983, its main metabolite.

Topics: Adult; Antipsychotic Agents; Benzamides; Blood-Brain Barrier; Corpus Striatum; Female; Humans; Male; Middle Aged; Oxazoles; Piperidines; Pyrimidines; Pyrrolidines; Receptors, Dopamine D2; Receptors, sigma; Schizophrenia; Tomography, Emission-Computed, Single-Photon