Identification of antipsychotic drug fluspirilene as a potential p53-MDM2 inhibitor: a combined computational and experimental study.

The inhibition of tumor suppressor p53 protein due to its direct interaction with oncogenic murine double minute 2 (MDM2) protein, plays a central role in almost 50 % of all human tumor cells. Therefore, pharmacological inhibition of the p53-binding pocket on MDM2, leading to p53 activation, presents an important therapeutic target against these cancers expressing wild-type p53. In this context, the present study utilized an integrated virtual and experimental screening approach to screen a database of approved drugs for potential p53-MDM2 interaction inhibitors. Specifically, using an ensemble rigid-receptor docking approach with four MDM2 protein crystal structures, six drug molecules were identified as possible p53-MDM2 inhibitors. These drug molecules were then subjected to further molecular modeling investigation through flexible-receptor docking followed by Prime/MM-GBSA binding energy analysis. These studies identified fluspirilene, an approved antipsychotic drug, as a top hit with MDM2 binding mode and energy similar to that of a native MDM2 crystal ligand. The molecular dynamics simulations suggested stable binding of fluspirilene to the p53-binding pocket on MDM2 protein. The experimental testing of fluspirilene showed significant growth inhibition of human colon tumor cells in a p53-dependent manner. Fluspirilene also inhibited growth of several other human tumor cell lines in the NCI60 cell line panel. Taken together, these computational and experimental data suggest a potentially novel role of fluspirilene in inhibiting the p53-MDM2 interaction. It is noteworthy here that fluspirilene has a long history of safe human use, thus presenting immediate clinical potential as a cancer therapeutic. Furthermore, fluspirilene could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against several types of cancer. Importantly, the combined computational and experimental screening protocol presented in this study may also prove useful for screening other commercially-available compound databases for identification of novel, small molecule p53-MDM2 inhibitors.

[Trichoma (Plica polonica) - a contemporary case with a historical disease]. / Der Weichselzopf (Plica polonica) - eine aktuelle Kasuistik zu einem historischen Krankheitskonzept.

We describe a 62-year-old patient with a chronic delusional disorder who presented with severely matted hair ("plica polonica"). Until the late 19th century such dreadlocks were considered as cause, consequence and treatment of mental disease. The historical development of "plica polonica" is briefly reviewed as an example of early and once popular psychiatric disease concepts.

Depot fluspirilene for schizophrenia.

BACKGROUND: Antipsychotic drugs are the mainstay treatment for schizophrenia and similar psychotic disorders. Long-acting depot injections of drugs such as fluspirilene are extensively used as a means of long-term maintenance treatment. OBJECTIVES: To review the effects of depot fluspirilene versus placebo, oral anti-psychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (September 2005), inspected references of all identified studies, and contacted relevant pharmaceutical companies. SELECTION CRITERIA: We included all relevant randomised trials focusing on people with schizophrenia where depot fluspirilene, oral anti-psychotics, other depot preparations, or placebo were compared. Outcomes such as death, clinically significant change in global function, mental state, relapse, hospital admission, adverse effects and acceptability of treatment were sought. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality rated and data extracted. For dichotomous data, we calculated relative risk (RR) with the 95% confidence intervals (CI). Where possible, the number needed to treat statistic (NNT) was calculated. Analysis was by intention-to-treat. We summated normal continuous data using the weighted mean difference (WMD). We presented scale data only for those tools that had attained pre-specified levels of quality. MAIN RESULTS: We included twelve randomised studies in this update of which five are additional studies. One trial compared fluspirilene and placebo and did not report important differences in the global improvement (n=60, 1 RCT, RR "no important improvement "0.97 CI 0.9 to 1.1). Though movement disorders (n=60, 1 RCT, RR 31.0 CI 1.9 to 495.6, NNH 4) were found only in the fluspirilene group, there were no convincing data showing the advantage of oral chlorpromazine or other depot antipsychotics over fluspirilene decanoate. We found no difference between depot fluspirilene and other oral antipsychotics with regard to relapses or to the number of people leaving the study early. Global state data (CGI) were not significantly different, in the short term when comparing fluspirilene with other depots (n=90, 2 RCTs, RR "no important improvement" 0.80 CI 0.2 to 2.8). No significant difference were apparent between fluspirilene and other depots with respect to the number of people leaving the trial early (n=83, 2 RCTs, RR 0.55 CI 0.1 to 2.3) or relapse rates (n=109, 3 RCTs, RR 0.55 CI 0.1 to 2.3). Extrapyramidal adverse effects were significantly less prevalent in the fluspirilene groups (n=164, 4 RCTs, RR 0.50 CI 0.3 to 0.8, NNH 5). Other adverse effects were not significantly different. Attrition in the one comparison between fluspirilene in weekly versus biweekly administration (n=34, RR 3.00 CI 0.1 to 68.8) and relapse rates (n=34 RR 3.18 CI 0.1 to 83.8) were not significantly different. There were no significant difference for movement disorders in one short term study. No study reported on hospital and service outcomes or commented on participants' overall satisfaction with care. Economic outcomes were not recorded by any of the included studies. AUTHORS' CONCLUSIONS: Participant numbers in each comparison were small and we found no clear differences between fluspirilene and oral medication or other depots. The choice of whether to use fluspirilene as a depot medication and whether it has advantages over other depots cannot, at present, be informed by trial-derived data. Well-conducted and reported randomised trials are still needed to inform practice.

Grief hallucinations: true or pseudo? Serious or not? An inquiry into psychopathological and clinical features of a common phenomenon.

An inquiry into the psychopathology and the clinical significance of grief hallucinations is presented and two cases with severe grief hallucinations are described. Unlike many cases in the literature, the two female patients were young (aged 43 and 45, respectively) and both suffered from the loss of a daughter. The heterogeneous concept of grief hallucinations is described and discussed, focusing particularly on the difficulties of reaching a differentiation between hallucination and pseudohallucination. Basic theses of the article are: (1) Contrary to a widely held view, grief hallucinations can display all the characteristics of 'true' hallucinations. (2) The concept of grief hallucinations probably comprises a heterogeneous group of disturbances of perception and of thought processes. They can be experienced as comforting but can also cause considerable distress. (3) There are essentially two definitions of pseudohallucinations and they contradict each other. The extremely vague concept of pseudohallucinations appears to be of questionable value and should be abandoned.

Depot fluspirilene for schizophrenia.

BACKGROUND: Anti-psychotic drugs are the mainstay treatment for schizophrenia and similar psychotic disorders. Long-acting depot injections of drugs such as fluspirilene are extensively used as a means of long-term maintenance treatment. OBJECTIVES: To assess the effects of depot fluspirilene versus placebo, oral anti-psychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. SEARCH STRATEGY: Relevant trials were identified by searching Biological Abstracts (1982-1998), Cochrane Library (Issue 2, 1998), Cochrane Schizophrenia Group's Register (June 1998), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). References of all identified trials were also inspected for more studies. SELECTION CRITERIA: All relevant randomised trials focusing on people with schizophrenia where depot fluspirilene, oral anti-psychotics or other depot preparations were compared. Outcomes such as death, clinically significant change in global function, mental state, relapse, hospital admission, adverse effects and acceptability of treatment were sought. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality rated and data extracted. For dichotomous data, Peto odds ratios (OR) with the 95% confidence intervals (CI) were estimated. Where possible, the number needed to treat statistic (NNT) was calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. MAIN RESULTS: Seven studies were included. Most comparisons included very few participants. There are no convincing data showing fluspirilene decanoate's advantage over oral chlorpromazine or other depot antipsychotics. No study reported on hospital and service outcomes or commented on participants' overall satisfaction with care. Economic outcomes were not recorded by any of the included studies. REVIEWER'S CONCLUSIONS: The total numbers in each comparison were small and there were no clear differences demonstrated between fluspirilene and oral medication or other depots. The choice of whether to use fluspirilene as a depot medication and whether it has advantages over other depots, cannot, at present, be informed by trial-derived data. Well-conducted and reported randomised trials are still needed to inform practice.

Side effects of low dose neuroleptics and their impact on clinical outcome in generalized anxiety disorder.

1. The present study was designed to determine the impact of neuroleptic side effects on clinical outcome in generalized anxiety disorder. 2. 205 outpatients entered the study. In an open label design fluspirilene 1.5 mg per week was administered for a period of 6 weeks. 3. Consistent with previous studies fluspirilene demonstrated again anxiolytic properties and was in general tolerated well. 4. However, in responders significantly less side effects were observed than in nonresponders. The interaction between tolerability and clinical outcome is the main finding of the present study. 5. In conclusion, the data suggest, that neuroleptic treatment of generalized anxiety disorder should be guided by paying more attention to potential side effects. If under neuroleptic treatment of generalized anxiety disorders side effects are observed, pharmacotherapy should be discontinued, because this fact predicts an unfavourable clinical outcome.

Test therapy in the treatment of generalized anxiety disorders with low dose fluspirilene.

1. The present double-blind study was designed to determine under three different conditions (0.5 mg, 1.0 mg, 1.5 mg per week) whether response or non-response within a two-week test-therapy predicts clinical outcome after 6 weeks of fluspirilene treatment in generalized anxiety disorders. 2. 106 outpatients entered the study. The period of observation was 6 weeks. 3. Confirming previous reports of their study group the authors found a significant reduction of anxiety in all treatment groups. However, this effect was mainly observed with the highest dose administered. The main finding of the study is that there is a significant correlation between initial response after 2 weeks of test therapy and therapeutic success after 6 weeks in fluspirilene treatment of generalized anxiety disorders. 4. Decreases in somatic anxiety, psychic anxiety and Hamilton-total-score within the first 2 weeks correlate with the baseline-to-week 6 decreases of the corresponding item and with the global clinical assessment of efficacy after 6 weeks. 5. By means of test therapy patients with an unfavourable outcome are identified and, if medication is discontinued, are prevented from an ineffective longterm treatment.

Delirio dermatozoo en pacientes con organicidad / Dermatozoon delusion in patients with organic injuries

Se presentan 2 pacientes con diagnostico de delirio dermatozoo, al realizar una revision de dicha entidad a proposito de la presentacion, en ambos casos aparece una asociacion causal con la afeccion organica. El tratamiento indicado con fluspirileno resulto novedoso y de buena evolucion, y no habia sido reportado con anterioridad

Low dose neuroleptanxiolysis in anxiety states.

1. In order to prove that neuroleptanxiolysis represents a therapeutical alternative in the treatment of patients suffering from anxiety we conducted four investigations. 2. In the first study it was experimentally proved with 45 outpatients suffering from anxiety that fluspirilene (1.5 mg per week) is superior to bromazepam (6 mg/day), especially in patients with a high degree of somatic anxiety. 3. In the second study the tolerance of fluspirilene (1.5 mg per week) was investigated in 1261 patients with anxiety states and psychoreactive disorders under controlled and open conditions for a period of six weeks. Side effects were found in 11.5% of the patients. All side effects had in common that they occurred already within the first few weeks of treatment. 4. In the third study investigating the dose-effect relationship 106 patients received either 0.5, 1.0, or 1.5 mg fluspirilene per week for a period of 6 weeks. The main result of this study was the verification of a clear dose-effect relationship. 5. The fourth study compared 155 patients who had received long-term treatment with fluspirilene (max 1.5 mg/week) and 121 patients with long-term benzodiazepine treatment. No differences were found with regard to the frequency and intensity of extra-pyramidal disturbances. 6. The therapeutical relevance of the findings was emphasized in the general discussion.

Papel de la enfermera en la clínica del IMAP / The role of the nurse at the IMAP clinic

Se realiza un estudio con los pacientes que reciben tratamiento con fluspirileno (IMAP) en el Dispensario de Salud Mental en el año que comprende desde el 1 de enero de 1987 hasta el 1 de enero de 1988: se analiza la evolución de los pacientes con este tratamiento y reacciones extrapiramidales presentadas, los ingresos que han causado a pesar de llevar el tratamiento y el criterio de los familiares en relación con el medicamento: se ofrece análisis estadístico de los resultados que se expusieron en tablas sobre el estudio efectuado

Utilization and safety of fluspirilene in nonpsychotic outpatients.

Over a six-month period, the utilization and safety of fluspirilene were investigated in 230 nonpsychotic outpatients in twelve private psychiatric practices. The patients treated under routine treatment conditions were about 20 years older than those included in experimental studies with this drug. In contrast to expert recommendations, 21.7% of the patients had received repeated injections of fluspirilene for longer than three months. A total of 46.1% of patients had been comedicated from time to time with antidepressants, while 30% had received benzodiazepines, indicating that fluspirilene is used as an alternative, but also as a supplementary treatment to benzodiazepine tranquilizers. Adverse reactions, probably related to fluspirilene, were recorded in 8.7% of patients and led to discontinuation of treatment in 3.9%. Disturbances of the extrapyramidal system predominated (in 5.6% of patients), with akathisia being observed most often (in 3.5%). It is concluded that the application of fluspirilene would seem to be safe if the drug is administered in the recommended way, but that there is a risk of tardive dyskinesias in the case of higher doses, longer duration of use, or pre-existing cerebral lesions (as manifested by two patients included in this survey).

Visual contrast sensitivity in drug-induced Parkinsonism.

The influence of stimulus orientation on contrast sensitivity function was studied in 10 patients with drug-induced Parkinsonism. Nine of the 10 patients had at least one eye with contrast sensitivity deficit for vertical and/or horizontal stimuli. Only generalised contrast sensitivity loss, observed in two eyes, was stimulus orientation independent. All spatial frequency-selective contrast deficits in 15 eyes were orientation dependent. The striking similarity between the pattern of contrast sensitivity loss in drug-induced Parkinsonism and that in idiopathic Parkinson's disease, suggests that generalised dopaminergic deficiency, from whatever cause, affects visual function in an analogous way.

Fluspirileno (IMAP) en el tratamiento de las crisis aguda de mania / Fluspiriline (IMAP) in treatment of acute maniac crisis

Se trataron 10 pacientes portadores de crisis agudas de manía mediante la administración de fluspirileno (IMAP), en dosis que oscilaron entre 12 y 16 mg utilizadas en un período no mayor de 7 días. Se utilizaron subdosis de 4 mg por vez y por vía intramuscular los días primero, segundo, cuarto, y cuando fue necesario también el séptimo, sólo en los casos que no hubiese remitido el cuadro clínico de manía aguda. Se observó una mejoría apreciable de la mayoría de los casos ya al quinto día, sin ninguna complicación ni manifestaciones de toxicidad, logrando sobre todo la desaparición de las ideas delirantes, la disforia y mejorando las relaciones sociales del paciente, perturbadas por su sistema delirante. En el 50% de los casos después de la administración de la primera dosis, se presentó un sueño prolongado y el rápido restablecimiento del ritmo del dormir perturbado por la crisis

Utilidad del tratamiento con fluspirilene: estudio comparativo / Usefulness of treatment with fluspirilene: comparative study

Se realiza un estudio a todos los pacientes esquizofrénicos que acudieron a recibir el tratamiento con el neuroléptico de depósito fluspirilene (IMAP), durante el año 1985. Se revisan sus historias clínicas para recoger las variables edad, sexo, ocupación, tiempo bajo el tratamiento, frecuencia de los mismos, dosis administrada, tratamiento previo y estado actual. También, se realizan encuestas a dichos enfermos y sus familiares para recoger criterios sobre este tipo de tratamiento. Se compara el grupo con uno de 82 pacientes diagnosticados igualmente como esquizofrénicos, con los mismos parámetros, pero que utilizaron neuroléoticos orales, en igual período. Se muestran en tablas las conclusiones más importantes y se destaca una diferencia significativa de los pacientes tratados con fluspirilene comparados con el grupo control en cuanto a la mejoría de los síntomas

Clinical symptomatology and drug compliance in schizophrenic patients.

The differences in the psychopathologic status of 26 complaint and 32 noncomplaint schizophrenic patients were evaluated on the basis of rating scales used at discharge. Noncomplaint patients had significantly higher scores for grandiosity, lack of feeling of illness and insight into it. Their score for global psychopathological state and disturbance in social adjustment was also significantly higher. The compliant patients had significantly higher score for self-rated depression.

A controlled clinical trial of fluspirilene, a long-acting injectable neuroleptic, in schizophrenic patients with acute exacerbation.

A 4-week double-blind controlled clinical trial was carried out in which fluspirilene, an injectable diphenylbutylpiperidine neuroleptic given weekly, was compared to chlorpromazine in the treatment of 40 newly admitted schizophrenic patients with acute exacerbation. Similar therapeutic improvement was obtained with both drugs, but men needed a significantly higher mean dose of fluspirilene (23 mg/week) than women (13 mg/week). Fluspirilene induced more parkinsonism than chlorpromazine, but less drowsiness, dizziness, and dry mouth. The difference between the sexes in the potency of fluspirilene and its greater potential to induce parkinsonism may be related to its lesser presynaptic and D1-dopamine receptor blocking properties. The low incidence of autonomic side effects confirms the relative specificity of fluspirilene for dopamine receptors.

Effects of six weeks' neuroleptic treatment on the pituitary-thyroid axis in schizophrenic patients.

In order to investigate the effects of 6 weeks' neuroleptic treatment on the pituitary-thyroid axis in 25 male schizophrenic patients, and the diurnal variation in the thyrotropin (TSH) and prolactin (PRL) responses to thyrotropin-releasing hormone (TRH) in these patients, the TRH stimulation test was performed in each of them at 14.00 and 24.00 h of the same day, both before and after 6 weeks' treatment with neuroleptics (chlorpromazine or fluspirilene). Also, serum thyroxine (T4), in vitro radioactive triiodothyronine uptake (RT3 U) and free-thyroxine index (FTI) values were estimated from the pre-TRH blood sample. We found no evidence of diurnal variation in the TSH response to TRH in the schizophrenic patients, before or after 6 weeks' neuroleptic treatment. Only drug-free schizophrenic patients had significantly higher PRL responses to TRH at 14.00 h than those at 24.00 h. After 6 weeks' neuroleptic treatment, schizophrenic patients tended to have lower FTI values; also, they had significantly higher basal TSH and PRL values, as well as significantly augmented TSH and PRL responses to TRH, in comparison to their pretreatment values. These findings render possible the diagnosis of subclinical hypothyroidism in neuroleptic-treated schizophrenic patients.

Experimental comparison of low doses of 1.5 mg fluspirilene and bromazepam in out-patients with psychovegetative disturbances.

In order to find out whether the administration of bromazepam and low doses of fluspirilene for six weeks had different effects, 45 out-patients of both sexes received 6 mg bromazepam per day or 1.5 mg fluspirilene per week in a double-blind randomized fashion. Overall therapeutic effectiveness was rated by the physician in two weeks' intervals. In addition use was made of the Hamilton Anxiety Scale, the Adjective List (Janke and Debus), and the Symptom Check List (Derogatis). Both products reduced anxiety in a comparable manner. Under fluspirilene, however, global therapeutic improvement was often more obvious than under bromazepam. This therapeutic superiority was particularly remarkable in patients whose somatic concern in the meaning of the Hamilton Anxiety Scale was comparatively pronounced.