Characterization of the sigma ligand panamesine, a potential antipsychotic, by immune response in patients with schizophrenia and by sleep-EEG changes in normal controls

Abstract

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.

Clinical Trials with Sigma Ligands

“…The compound of this group of sigma-ligands that has been investigated most thoroughly is panamesine (EMD 57 445). Four clinical trials [5,6,12,20] have been published so far. Since the trial of Frieboes et al [6] was not primarily aimed at establishing clinical efficacy but at the characterization of the effects of panamesine on the immune system and on sleep EEG-parameters in healthy volunteers, this trial will not further be discussed.…”

“…Igmesine, Cl-1 019, JO-1 784 Highly selective sigma ligand, sigma-1-agonist (functional) diarrhea [22] Depression [21] Panamesine High affinity sigma ligand, no sigma subtype specificity Schizophrenia [5,6,12,20] Siramasine, LU 28 ± 179 Sigma-2-opioid agonist Anxiety [11] SL 82.0715 Opiate sigma-receptor-antagonist Schizophrenia [16] BW 237U, rimcazole Selective but relatively weak sigma receptor antagonist Schizophrenia [2] DuP 734 Sigma-1-and 5-HT 2 -antagonist Schizophrenia [7] BMY 14 802 Sigma-receptor-ligand Schizophrenia [7] Opipramol Sigma-1/-2-ligand Depression Menopausal syndromes General anxiety disorders (GAD) Somatoform disorders (SD) Premedication on the evening prior surgergy [4,8,17,18,24] infusion. Data given as means, n = 8 subjects studied twice in random order at 24 hours-interval in a cross-over design (modified according to RozØ et al [22]).…”

Subchronic Effects of Olanzapine on Sleep EEG in Schizophrenic Patients with Predominantly Negative Symptoms

“…However, the sleep EEG abnormalities cited above are not specific for schizophrenia as they were also found in other psychiatric disorders [3]. Recent studies have reported the sleep-consolidating effects of antipsychotic drugs in schizophrenic patients and in healthy subjects [10,25,32]. Generally, the sleep-consolidating properties consist of improved sleep continuity and efficiency due to increased non-REM (NREM) sleep.…”

Imaging Sigma Receptors: Applications in Drug Development

“…A 1997 open clinical trial, 5/12 patients were judged as responders (50% decrease in the BPRS score), six patients showed only slight improvement in symptoms, and one deteriorated [155,156]. No major side effects were observed.…”

“…Indeed, many potential antipsychotic agents with atypical therapeutic profiles in rodent models and humans bind sigma-1 receptors with moderate to high (nM) affinity. Examples include rimzacole [146], remoxipride [147], BMY 14802 [147], NE-100 [120,123,124,[148][149][150][151][152][153][154], panamisine (EDM 57445) [122,155,156], and SL82.1705 [157]. Perhaps selective binding to this site is not enough to alleviate symptoms, but it is possible that a drug with mixed sigma receptor binding and activity at other receptors or transporters might be appropriate.…”