A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects.

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography-tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC50 of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC50 of 9.2 µM. Despite inhibiting hERG tail current at an IC25 of 3.2 µM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 µM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.

Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study.

Ketamine and its enantiomer esketamine have gained much attention in recent years as potent, fast-acting agents for the management of treatment-resistant depression. However, an alternative to oral ketamine administration is required to ensure adequate systemic exposure as the drug undergoes extensive first-pass metabolism. We propose dry powder inhalation as a new esketamine delivery route. Here, we examine the pharmacokinetics, pharmacodynamics, toxicology and safety of this novel esketamine administration method. Esketamine (10 mg/kg) and ketamine racemate (20 mg/kg) were administered to rats by dry powder inhalation, intravenous injection or intratracheal instillation and the pharmacokinetics of these treatments were compared. Analyte concentration of ketamine stereoisomers and their metabolites was assessed by LC-MS/MS method. Esketamine showed a clinically relevant pharmacokinetic profile, with high bioavailability (62%) and relatively low maximum concentration peaks. Esketamine exhibited high penetration of the blood-brain barrier, but pharmacodynamic examinations of brain homogenates showed no changes in selected protein phosphorylation or expression analyzed by the immunoblotting method. We conducted GLP-compliant 14-day and 28-day general toxicity studies in rats and dogs, respectively, subjected to dry esketamine powder inhalation. The maximum daily dosages were 46.5 mg/kg and 36.5 mg/kg, respectively. We also performed pharmacological safety studies. Esketamine inhaled as dry powder had an expected safety profile consistent with its known pharmacological action. None of its observed effects were considered toxicologically significant. The pharmacological safety studies confirmed that the observed effects were transient and that inhaled esketamine had a good safety profile. Hence, our preclinical studies demonstrated that dry powder inhalation is a highly efficacious and safe delivery route for esketamine and may be a viable alternative administration route meriting further clinical development.

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists.

TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF's action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 µM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.

Social and medical determinants of quality of life and life satisfaction in women with Turner syndrome.

BACKGROUND: Turner syndrome (TS) appears in women as a result of the lack of part or the whole of one of the X chromosomes. It is characterized by the occurrence of low height, hypogonadism, numerous developmental defects, and is often accompanied by psychological disturbances. OBJECTIVES: Although the phenotype characteristics of women with TS are quite well documented, the knowledge of the impact of Turner syndrome on the satisfaction with life is still insufficient. The aim of our study was to assess the impact of TS on selected variables of quality of life, and hence also life satisfaction in women with this syndrome. MATERIAL AND METHODS: The research was carried out in a group of 176 women with TS starting March 1995. The patients underwent anthropological and medical examinations, and their medical histories were taken using a questionnaire that included demographic and psychosocial items as well as issues related to selected variables of quality of life. In our research model, general life satisfaction was a dependent variable. The statistical analysis was conducted using the eta and Cramer's V correlation coefficients as well as a multidimensional logistic regression model. RESULTS: The main determinants of dissatisfaction with life in women with TS were short stature and feelings of loneliness and being handicapped. CONCLUSIONS: The determinants of life satisfaction in women with Turner syndrome were closely related to the private life of the study participants, in particular self-perception and feelings concerning their health status.

Knowledge of cancer symptoms and anxiety affect patient delay in seeking diagnosis in patients with heterogeneous cancer locations.

PURPOSE: This research was aimed at identifying factors that predict patient delay in treatment initiation in patients with suspected cancer disease. We sought to determine the differences between delaying and nondelaying patients with reference to their knowledge of cancer symptoms, sociodemographic variables, and the levels of state anxiety and trait anxiety. METHODS: The study involved 301 randomly selected patients with suspected cancer disease before their first oncology appointment at a regional oncology center in Poland. Data were collected by means of a semistructured interview conducted by a trained psychologist. To evaluate the knowledge of cancer symptoms, the symptoms mentioned by subjects were compared to the list of symptoms from cancer awareness measure. Anxiety levels were assessed using the State-Trait Anxiety Inventory. RESULTS: In the course of logistic regression analysis a model was developed, in which knowledge of cancer symptoms and state anxiety allowed to predict patient delay. Knowledge of every additional cancer symptom decreased the chance of patient delay by 16.4% point [95% CI: 1.4-29.2]. An increase in state anxiety for every point of the scale decreased the chance of delay by 2.5% points [95% CI: 0.2-4.6]. Trait anxiety and the studied sociodemographic variables proved to be nonsignificant predictors of patient delay. CONCLUSIONS: Knowledge of cancer symptoms and the level of state anxiety allowed to predict patient delay in the initiation of treatment. Owing to the heterogeneity of the tumor locations within the sample, the obtained model can be used in large scale prevention programs designed for the whole population.

Olfactory bulbectomy-induced changes in phospholipids and protein profiles in the hippocampus and prefrontal cortex of rats. A preliminary study using a FTIR spectroscopy.

BACKGROUND: Dysfunctions in neuronal proteins can lead to development of depression. Lipids determine the localization and function of proteins in the cell membrane and thereby regulate synaptic throughput in neurons. The aim of study was to examine changes in the phospholipid-protein balance in the olfactory bulbectomy (OB) model of depression in rats using a Fourier transform infra-red (FTIR) spectroscopy. METHODS: Sprague Dawley rats were subjected to the OB procedure and treated with amitriptyline (AMI, 10mg/kg). The FTIR measurements were performed in the hippocampus and prefrontal cortex. RESULTS: The obtained results show a decrease in the phospholipids and protein fractions (as well as changes in their secondary structures) in both brain areas of bulbectomized rats. AMI treatment reduced phospholipids' and increased the proteins' brain level, yet did not affect the level of phospholipids or increase the proteins in OB rats. Second derivatives calculated from the FTIR spectra provided information that the proteins (but not phospholipids) in both structures of the OB_AMI rats were normalized after antidepressant treatment. CONCLUSIONS: Our findings prove that the changes in the phospholipid-protein balance in the hippocampus and prefrontal cortex may be related to depressive disorders, thus leading to the development of adverse changes in the molecules necessary for the correct functioning of the brain. Furthermore, these results suggest a stability of the structure changes/damage of phospholipids in depression, which are present in brain tissues even after effective pharmacotherapy. This study also shows that an infrared spectroscopy can be applied for monitoring changes in mood disorders.

Types of reactions to malignant disease in view of V.E. Frankl philosophy.

PURPOSE: The purpose of this work was to find out whether there is interdependence between the patients- assessments of biological, psychological, psychosocial and spiritual levels. METHODS: 590 subjects, both ill and healthy, were examined by appropriate means and asked to consider their level of fear, depression (Hospital Anxiety and Depression Scale - Modification), aggression, quality of life (EORTC QLQ-C30 questionnaire), and the purpose and meaning of life (The "PURPOSE in Life Test" - PIL questionnaire). RESULTS: Three groups of patients were established with the help of statistical procedures. The first group encompassed the healthy subjects, whereas the second and third included those that were ill. Although the subjects estimated their level of physical fitness and general quality of life similarly, there were some essential differences in their disease-associated reactions (i.e. the groups adjusted differently - the second group poorly and the third well). The majority of people suffering from cancer were well adapted to the early stages of the disease. As cancer progressed the percentage of those that adjusted poorly rose. However, even in the terminal stage some of the patients, about 1/3, still belonged to the group of those that were quite well adjusted. Established meaning of life, system of values, and personal religion were factors that helped to adapt. CONCLUSIONS: There was no connection between the patients' assessments of their biological level and other (psychological, psychosocial, spiritual) levels. We can distinguish groups of patients that judge their physical condition similarly and still vary in the assessment of their emotional state or meaning of life.

Anxiety disorders in intimate partners and the quality of their relationship.

BACKGROUND: The aim of this study was to explain whether anxiety disorders presenting in one or both partners of a relationship can influence the latter and to what extent. METHODS: This study included 85 couples, where: 1) the male partner suffered from an anxiety disorder and female partner was free from this type of disorder (F((-))M((+)), n=20); 2) the female partner suffered from an anxiety disorder and the male partner was free from this type of disorder (F((+))M((-)); n=40); and 3) both partners were affected with anxiety disorders (F((+))M((+)), n=25). The quality of the relationship was assessed by both partners using three different scales: 1) Dyadic Adjustment Scale (DAS), 2) Family Attitude Scale (FAS), and 3) Marriage Success Scale (SPM). RESULTS: In case of the SPM scale, women from F((-))M((+)) group evaluated their marriages significantly compared to other groups. In case of males, the self-evaluated quality of marriage was the lowest in the case of individuals from F((+))M((+)) group. In case of the DAS scale, women and men being free from anxiety disorders assessed the quality of their relationships significantly higher than other participants. The analyzed groups did not differ significantly in terms of mean values scored in the FAS scale. LIMITATIONS: The lack of a multifactorial analysis taking into account the effects of a variety of anxiety disorders. CONCLUSION: The presence of anxiety disorders in at least one partner negatively affects the quality of partner relationship. The couples where the female partners are affected are particularly fragile.

Quality of life in patients with advanced lung cancer treated at home and at a palliative care unit.

BACKGROUND: To assess quality of life (QOL) in patients with advanced lung cancer. PATIENTS AND METHODS: A prospective study of 78 patients cared at home and at a palliative care unit (PCU) with 2 QOL assessments was conducted. RESULTS: Fifty patients completed the study. In the EORTC QLQ-C30 role, cognitive, social functioning, global QOL, fatigue, pain, dyspnea, and appetite deteriorated; nausea/vomiting improved; dyspnea was more intense in the case of in-home patients. In the EORTC QLQ-LC13 hemoptysis improved; pain in other parts was more intense in the PCU patients. Pain (Visual Analogue scale) was more intense in the PCU patients; the level of activity (Karnofsky) decreased in the case of patients treated at home. CONCLUSIONS: QOL deteriorated with few differences between home and the PCU patients.

Cerebrovascular pulsation and width of subarachnoid space during electroconvulsive therapy.

BACKGROUND: The mechanism of electroconvulsive therapy (ECT) has not been comprehensively explained. A new noninvasive method of monitoring intracranial homeostasis during and after ECT provides additional insight into the mechanism of ECT. The investigations on changes in the width of the subarachnoid space (SAS) and intracranial pulsation amplitude by near infrared-transillumination/backscattering sounding method can throw new light on changes in type and volume induced by ECT. METHOD: In this study, a new method of noninvasive investigation of width of SAS and intracranial pulsation parameters was used. This method has been called near infrared-transillumination/backscattering sounding. The method consists of light beam analysis in near infrared whereby the light beam is emitted by an emitting diode. The light beam passes through head's anatomic layers, is reflected multiple times in SAS, and returns outward-to be recorded by the receiving diode. The novelty of this method is the patented invention that allows skin flow under the probe to be eliminated and thereby "to look" under the skull bone. RESULTS: After ECT, a highly significant increase in pulsation amplitude was observed. The pulsation amplitude rose by a factor of 2.5 times after a mean of 90 seconds after the ECT stimulus. A pause in SAS pulsation-not longer than 26 seconds-directly after administration of electroshocks was observed. After approximately 90 seconds, the amplitude decreased slowly, and this was consistent in all analyzed cases. A decrease in SAS width was also observed.

The relationship between suicidal attempts and menstrual cycle in women.

The purpose of the study was to explore relationship between the menstrual cycle and suicidal attempts. A study was performed on 151 fertile females who were admitted to the Clinic of Internal Diseases and Acute Poisonings Medical University of Gdansk during the years 2002-2003 because of suicidal attempts. The inclusion criteria were as follows: fertility, regular menstrual cycle, lack of oral contraceptives, willingness to attend the follow up and willingness to see a psychiatrist. Using the anamnesis the patients were also grouped according to the menstrual cycle into menstrual, follicular, midcycle and luteal phase. According to psychiatric investigations every female was classified to the respective category: situational reaction, depression, schizophrenia, alcohol addiction and sociopathy. Severity of intoxication was classified according to Poisoning Severity Score (PSS). Statistical analysis was done with the use of chi-square test with Pearson correction. Suicidal attempts were the most frequent among females during menstrual phase. The most common diagnosis in females who have attempted suicide were situational reactions which dominated in patients aged 14-21 years. Among attempters with the psychiatric diagnosis of depression, schizophrenia and alcohol addiction the degree of poisoning was significantly more severe than in the patients with situational reaction.

A magnetic resonance volumetric study of the temporal lobe structures in depression.

Depression is one of the most common psychiatric disorders and is associated with considerable morbidity. In recent years structural-imaging technology has provided an opportunity to examine the brain anatomy in patients with the psychiatric illness. 10 patients of various ages and, as the control group, 16 healthy subjects were examined using the MRI method of neuroimaging. The volumes of the following structures were evaluated in the right and left hemispheres: the superior temporal gyrus, the basolateral temporal area (the region including middle temporal gyrus, inferior temporal gyrus and fusiform gyrus), the parahippocampal gyrus, the hippocampal head, the amygdaloid body and the lateral ventricle. The significant difference between the control group and the group with depression concerned the volume of the temporal horn of the lateral ventricle of both hemispheres. In depressed patients the left temporal horn was 49.8% and the right 38.4% larger in comparison with the control group. In the control group there were significant differences between the left and right hemispheres in the volume of all the structures studied, whereas in the group with depression these difference in volume between the hemispheres concerned only the amygdaloid body and the lateral ventricle.

[Relationship between medical students and patients during the course of psychiatry--expectations and fears]. / Kontakt studentów medycyny z pacjentami w czasie zajec z psychiatrii--oczekiwania i wzajemne interakcje.

AIM: The aim of this study was to discover methods of preparing medical students for contacts with mentally ill people and to create educational procedures considering the exceptionality of the course of psychiatry. METHODS: The examined group consisted of IVth, Vth, VIth-year students of the Medical University in Gdansk. We have analysed a group of 121 students. To perform our study we have created a questionnaire with 22 questions (enclosed). CONCLUSIONS: We have founds as follows: 1. Most of the students were at first interested in the subject; 2. Almost all of the students have actively participated in conversation with the patients; 3. Many of the students were afraid of relations with the patients; 4. The most difficult cases for the students were schizophrenic psychoses and affective diseases; 5. In the students' opinion there should be less than 4-6 students in a group; 6. In the students' opinion the time spent on conversation with one patient was too short.

[Prognostic value of pharmaco-EEG in depression treated with moclobemide]. / Analiza czynnosci bioelektrycznej mózgu u pacjentów leczonych moklobemidem.

Ten women (age 41.90 +/- 5.67) with depressive episode (moderate, mild; ICD-10) were treated with moclobemide (450 mg). After 4 weeks two groups (each consists of 5 patients) with different response to the drug emerged (responders: improvement in Beck Inventory of Depression 13.6 +/- 2.9 and nonresponders: 2.0 +/- 2.4). FFT analysis of their EEG (taken before and after 4 weeks of treatment) showed some relative power differences in most bands of frequencies between groups, mostly marked for á (7-14 Hz), smaller for ä and â, but no differences for è were found. Alfa activity was relatively low after treatment in nonresponders and slightly higher in responders. However any of these results had statistical value.

[Specificity of depression treatment in elderly population]. / Specyfika leczenia depresji wieku podeszlego.

Aging of population is one of the most important reasons for the increased incidence of depression observed in recent years. In 1994, 11% of Polish population aged 65 years or more. A similar tendency has been observed in other countries. These data prove the importance of depression in elderly people and its significance as a clinical as well as social problem. Depression in the elderly, in comparison to younger people, characterizes with a more variable and, usually, a more complex etiology. It is difficult to estimate the influence of aging, with all accompanying physical consequences, on the development of depression. Changes connected with aging are considered factors contributing to development of this disease and not its direct reason. According to Puzynski (1979), there are two major clinical patterns of depression in the elderly: depression with delusions and motional anxiety and depressive-astenic syndrome. The diagnosis of depression in the elderly is not easy. Classical symptoms of depression are becoming less clear and distinctive with aging. When treating depressive elderly people, it is important to remember about psychosocial influence, social therapy and psychotherapy directed to improve patient's self-esteem and create a positive image of future and surrounding world.